A Survey of the Structures of US FDA Approved Combination Drugs

Subscriber access provided by Bibliothèque de l'Université Paris-Sud

Perspective

A Survey of the Structures of US FDA Approved Combination Drugs Pradipta Das, Michael Delost, Munaum Qureshi, David Townsend Smith, and Jon T. Njardarson J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b01610 • Publication Date (Web): 16 Nov 2018 Downloaded from http://pubs.acs.org on November 17, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

A Survey of the Structures of US FDA Approved Combination Drugs Pradipta Das, Michael D. Delost, Munaum H. Qureshi, David T. Smith and Jon T. Njardarson* Department of Chemistry & Biochemistry, 1306 E. University Blvd., University of Arizona, Tucson, Arizona 85721, United States

ABSTRACT Combination drugs are an important class of US FDA approved pharmaceuticals. These drugs have been on a continuous growth trajectory since the first combination drugs were approved in the 1940s. In this perspective, we report the first comprehensive compilation and analysis of US FDA approved combination drugs, from the first approval in 1943 through 2018. Our database contains 419 combination drugs, which are represented by 328 unique small molecule structures. Breakdown of these drugs according to disease category, structure, combination composition and year of approval is presented as well as the top 24 most commonly used small molecule combination drug components. For frequently used small molecule components we present “relationship diagrams” to aid in the visualization of the many drug combinations these structures are part of. The main body contains eleven disease-focused sections wherein every small molecule component utilized as part of a combination for each disease category is displayed.

ACS Paragon Plus Environment

Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 135

INTRODUCTION: In our ongoing quest to create new educational and research content using the graphical language of organic chemistry,1 we have compiled for this perspective a comprehensive list of US FDA approved combination drugs (1940 – September 2018). Surprisingly, our survey of the literature revealed that the small molecule structural composition of this important category of drugs has previously not been presented or analyzed. A summary of the composition of this combination drug collection is graphically depicted in Figure 1. The collection contains a total of 419 FDA approved combination drugs, out of which 367 are structurally unique combinations. These 367 combinations are represented by only 328 small molecules. Analysis of this important small molecule dataset reveals high representation of aromatic moieties (78%) and nitrogen heterocycles (58%) and the majority of structures (53%) contain at least one asymmetric stereocenter. Oxygen heterocycles are less represented (19%) than their nitrogen heterocyclic counterparts. Beyond the four common atoms of life (C, H, N and O), this collection has rich representation of small molecules containing sulfur atoms (19%), almost twice that of fluorine atoms (10%).

Figure 1. Graphical Breakdown of US FDA Approved Small Molecule Combination Drugs Figure 2 presents the distribution of the 419 US FDA approved combination drugs2 as a function of the decade when they were approved and the disease category they belong to, which is represented by the color-coded ACS Paragon Plus Environment

Page 3 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


portion of each bar. Cancer chemotherapy combinations are not included in the introductory figures as a disease category. Although chemotherapy agents are FDA approved as monotherapies and widely used in combination regimens, only a few are approved as combination therapies. However, an extended discussion of the landscape of cancer combinations, past, present and future, appear at the end of this review. What is evident from this graphical representation is that this category of pharmaceuticals has been growing steadily since the first combination drugs were approved. The highest growth rate occurred between the 1940s and 1950s (375%); the lowest growth rate occurred between the 1960s and 1970s (9%). A possible explanation for the initial surge of combination drug approvals followed by a slowed rate can be the FDAs new stringent criteria and approval guidelines in 1971. In the 1950s and 1960s, there was controversy surrounding drug manufacturers and the FDA promoting antibiotic combinations despite a lack of strong evidence supporting that combinations were superior to each drug separately. As of 1971, strong evidence is needed to show that a combination drug offers a therapeutic benefit compared to each individual drug entity.3 In 1943, hycodan (homatropine + hydrocodone) became the earliest combination to be approved. However, it has since been discontinued. The next combination drug that was approved in 1948 (cafergot = ergotamine + caffeine) is still on the market. The most recent approved drug included in our survey, delstrigo (doravirine + lamivudine + tenofovir disoproxil fumarate) was approved in 2018 to treat HIV-1 infection for adults. In the 1940s, only two disease categories (nervous and respiratory systems) were represented by the four combination drugs approved. The 1990s marked the first decade that treatments for all ten disease categories (excluding cancer) were represented. Both nervous and respiratory system combinations have appeared in every decade. In the current decade (2010-2018) there is a major increase in the number of antiinfective combination drugs being approved and a large increase in respiratory system, endocrine system and genito-urinary and sex hormone drug combinations. Approval of cardiovascular drugs is in sharp decline during the current decade.



Page 4 of 135

Figure 2. Number of Combination Drugs Approved by Decade US FDA approved combination drugs are composed of two or more small molecules with individual International Nonproprietary Names (INNs). The detailed breakdown of these three categories is illustrated in Figure 3, which reveals that combination drugs with two small molecules represent the clear majority (81%), followed by combination drugs containing three (16%) and four (3%) INNs respectively. Combinations with two INNs are quite evenly distributed between all eleven disease categories with drugs treating nervous system (17%, salmon) and cardiovascular (17%, blue) conditions leading the way followed by anti-infective (12%, orange) and respiratory system (12%, green) drugs. Least represented in this category, and not represented in other categories, are combination drugs used to address musculo-skeletal (3%, grey) type conditions. Combinations composed of three small molecules are represented by eight disease categories of which the majority are prescribed for antiinfective (40%, orange) or nervous system (24%, salmon) conditions. There are only eleven combination drugs ACS Paragon Plus Environment

Page 5 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


containing four small molecules, out of which six (55%, orange) are anti-infective agents. Closer inspection of these complex combinations reveals that infective diseases such as hepatitis C and human immunodeficiency virus-1 (HIV-1) are typically treated with more drug components. Furthermore, half of the anti-infective combinations containing three or four small molecules have been approved within the last decade. This signifies that ongoing research dedicated to the treatment of serious infections such as hepatitis C and HIV-1 has continued to be a priority.

Figure 3. Frequency and Disease Distribution of Combination Drugs with 2, 3 and 4 Small Molecule Components A closer look at the relative impact seventy-five years (1943-2018) of combination drugs has had on disease categories is presented in Figure 4. Combination drugs approved to alleviate symptoms associated with nervous system (19%, salmon) or anti-infective (18%, orange) conditions are the most highly represented disease categories followed by cardiovascular drugs (15%, blue). These three disease categories, which correspond to 52% of all approved combination drugs, are the areas of medicine where combination drugs have had the most success to date. The 4th and 5th ranked disease categories in terms of the number of combination drugs are the respiratory system (11%, green) and genito-urinary and sex hormone (9%, yellow) categories. About the same number of combination drugs (5-7%) have been approved for sensory organ (light blue), alimentary tract and metabolism (dark green), endocrine system (purple) and dermatological (brown) conditions. ACS Paragon Plus Environment


Page 6 of 135

Figure 4. Distribution of US FDA Approved Combination Drugs According to Disease Category. Although the same INNs are represented multiple times in many combination drugs, the distribution of the INNs is far from even. Some molecules punch above their weight and appear in a high amount of US FDA approved drug combinations. To aid in visualizing this privileged class of small molecules we have created a top 24 list ranked according to the number of combinations these drugs appear in (Figure 5). Although these twentyfour small molecules represent only 7% of the total number of unique small molecules approved, they remarkably are found in 76% of the combination drugs. From a structural standpoint, these heavy hitters are interesting as well. For example, the majority (62%) of these structures are chiral, while 66% contain at least one aromatic ring. Nitrogen heterocycles are significantly represented (38%) and appear in almost twice as many of these prevalent structures than oxygen heterocycles (21%). Four (16%) of these 24 compounds, including the most abundant (hydrochlorothiazide) are decorated with at least one sulfur atom while only one (#15, emtricitabine) is substituted ACS Paragon Plus Environment

Page 7 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


with a fluorine atom. Natural products (neomycin, polymyxin B, codeine, caffeine and hydrocortisone) and natural product derivatives play a significant role among these top structures with sixteen (58%) belonging to this category, including six steroids and two opioids. The primary differences between the structural diversity of the top 24 compared to all the combination drug components are more chiral structures (62% vs. 53%) and less representation of nitrogen heterocycles (38% vs. 57%) and fluorine substituents (1% vs. 9%). A possible explanation for lower percentages of fluorine substituents in the top 24 could be the lack of efficient fluorination methods available during the time these pharmaceuticals were developed. The development of scalable fluorination methods (especially late-development fluorination methods) continues to be pursued.4 The top five combination drug components are hydrochlorothiazide, neomycin, pseudoephedrine, aspirin and polymyxin B, which appear in 35, 24, 23, 20 and 19 combination drugs respectively, which overall is an astonishing 121 (29%) total number of combinations. Almost all hydrochlorothiazide-containing combinations are used to treat cardiovascular conditions while neomycin and polymyxin, which are anti-infectives, also target infections in sensory organ and dermatological areas.



Page 8 of 135

Figure 5. Top 24 Most Frequently Utilized Small Molecule Combination Drug Components To better aid in visualizing some of these top 24 privileged small molecules and their respective combination drug partners, we have created several structure-based “relationship diagrams” which include information about disease categories as well as the names of associated combinations. Hydrochlorothiazide Combinations: Hydrochlorothiazide, a member of the thiazide family of diuretics first approved in 1958, is used both alone as well as in combination with various cardiovascular drugs to treat hypertension and heart failure.5 HCTZ and HCT are both used as an abbreviation for hydrochlorothiazide; HCTZ is used when the compound itself is abbreviated, and HCT is used when hydrochlorothiazide is present in a combination drug. The combination ACS Paragon Plus Environment

Page 9 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


structure relationship diagrams for hydrochlorothiazide are presented in Figures 6A and 6B. Thirty-three unique drug combinations with hydrochlorothiazide have been approved, with the majority being indicated for cardiovascular treatment. Twenty-nine (88%) of combinations contain three components total; the remaining four (12% contain) contain four components total. Overall, eleven structural classes and two disease categories (cardiovascular and endocrine) are represented. Hydrochlorothiazide has been combined with beta blockers (propranolol, pindolol, labetalol, metoprolol and bisoprolol and timolol), angiotensin-converting enzyme (ACE) inhibitors (captopril, moexipril, enalapril, benazepril, quinapril, fosinopril and lisinopril), Angiotensin-II receptor antagonists (eprosartan, losartan, irbesartan, valsartan, candesartan, telmisartan and olmesartan), a renin inhibitor (aliskiren), a calcium channel blocker (amlodipine), natural products (reserpine and deserpidine), other diuretics (amiloride, spironolactone and triamterene), as well as various other antihypertensive drugs (guanethidine and hydralazine). ACE inhibitors were discovered after John Vane showed that the venom of the Brazilian viper, Bothrops jararaca inhibited ACE in dog lungs. The first ACE inhibitor, captopril was launched in 1981.6 Three years later, captopril went on to become the first ACE-inhibitor to be used in combination with HCTZ. Aliskiren, the first and only renin inhibitor, was approved 109 years after renin was first discovered in 1898. Even after aliskiren was discovered in 1993, it took fourteen years to finally be approved. This was because after Ciba and Sandoz merged to form Novartis in 1996, valsartan, not aliskiren was chosen to be developed. In 1999, former Ciba employees founded Speedel to continue developing aliskiren. In 2003, after successful phase I clinical trials and improved process chemistry, aliskiren was licensed back to Norvartis.7 Aldoril (methyldopa + hydrochlorothiazide), approved in 1962 but later discontinued, was the first hydrochlorothiazide combination to be approved. The other component, methyldopa, was used as an -2 adrenergic receptor agonist. In 1965, dyazide (triamterene + hydrochlorothiazide) became the earliest combination to contain an additional diuretic (triamterene). In 2010, tribenzor (olmesartan + amlodipine + hydrochlorothiazide) and amturnide (aliskiren + hydrochlorothiazide + amlopidine) became the latest HCTZ combinations to be approved. There are various rationales for combining thiazides especially HCTZ with other agents. It has been shown that combining HCTZ with another antihypertensive agent with a different mechanism of action can increase blood pressure responses.8 Although thiazides are cost-effective as well as extremely effective, taking them as a full dose monotherapy ACS Paragon Plus Environment


Page 10 of 135

regimen can often lead to undesirable side-effects which ultimately leads to patients no longer willing to take the drug. Therefore, combining a diuretic with another mechanistically distinct antihypertensive agent lowers the dose of diuretic given which reduces undesirable side effects. Furthermore, the other drug added can reduce side effects of HCTZ. For example, ACE inhibitors can help negate the oxidation activity of HCTZ as well as its propensity to lower potassium serum levels.9


Page 11 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 6A. Combination Structure Relationship Diagram for Hydrochlorothiazide Containing 2 INNs


Page 12 of 135

Figure 6B. Combination Structure Relationship Diagram for Hydrochlorothiazide Containing 3 INNs

Pseudoephedrine Combinations: Pseudoephedrine, a substituted phenethylamine, is used as a nasal decongestant both by itself as well as in combinations.10 Pseudoephedrine is part of 23 unique combinations, highlighted in Figure 7, belonging to six structural and two disease categories (respiratory and nervous system) respectively. Majority of these combinations (74%) contain an antihistamine component, whose structural cores are in most cases a 1,1-diaryl 1,1-dialkylamine motif. Pseudoephedrine + antihistamines has been shown to be an effective combination in treating seasonal allergic rhinitis (SAR) through complementary mechanisms. Pseudoephedrine can treat nasal congestion associated with SAR but has no effects on histamine. Antihistamines can treat SAR but are ineffective as nasal decongestants.11 Earliest such antihistamine cores were substituted with short linear terminating tertiary amines, while later ones contained heterocyclic trialkylamine groups (piperidine, pyrrolidine or piperazine) with the two aryl rings being connected by a more rigid 1,1-ethylene linker. First generation antihistamines (brompheniramine, chlorpheniramine, dexbrompheniramine, clemastine and triprolidine) suffered from sedation side effects because of their ability to penetrate the blood brain barrier.12 Second-generation antihistamines, such as acrivastine, cetirizine and fexofenadine, have limited blood brain barrier permeability as a result of their hydrophilic carboxylic acid groups, which minimizes the risk of unwanted sedation.13 Loratadine, which contains ACS Paragon Plus Environment

Page 13 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


an additional rigid seven-membered ring, is also a second-generation antihistamine with limited potential for sedation. Loratadine contains a carbamate which is metabolized in vivo to the amine. Levocetirizine (an enantiomer of cetirizine) and desloratadine (a metabolite of loratadine) are referred to as third generation antihistamines. Pseudoephedrine combinations with non-steroidal anti-inflammatory drugs (NSAIDs) help control pain and inflammation. Advil C. S. and aleve C. S., which partner pseudoephedrine with ibuprofen and naproxen respectively, were approved in 1989 and 1999 and serve as examples of this combination. A triple combination (advil A. S.) was approved in 2004, which added chlorpheniramine as the third component with ibuprofen. Morphinan members codeine, hydrocodone and dextromethorphan (DM) act as antitussive cough suppressants, while guaifenesin acts as an expectorant in various combinations. In 1950, chlor-trimeton (pseudoephedrine + chlorpheniramine) became the first pseudoephedrine-containing combination to be approved. However, chlor-trimeton has since been discontinued. Thirty-four years later, triacin-C (codeine + pseudoephedrine + triprolidine), became the first pseudoephedrine combination to contain a morphinan member (codeine). In 2015, hycofenix (pseudoephedrine + guaifenesin + hydrocodone), became the latest pseudoephedrine combination to be approved. As shown in Figure 7, many famous drugs such as allegra D, mucinex D, aleve C.S, advil A.S, zyrtec-D, and claritin D contain pseudoephedrine as one of the drug components.



Figure 7. Combination Structure Relationship Diagram for Pseudoephedrine


Page 14 of 135

Page 15 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Acetaminophen Combinations: Acetaminophen, originally released in 1953, is an analgesic used to treat pain and fever conditions.14 It has been approved as a component of fifteen combination drugs, all of which are used to treat pain. Several structural classes (as indicated by color), are represented in the structure relationship diagram (Figure 8), including natural products (codeine and its derivatives, caffeine and pseudoephedrine), 1,1-diaryl anti-histamines, aspirin and a barbiturate (butalbital). About half (53%) of the combinations are composed of two components, 40% contain three components, and only one is approved with four components (fioricet w/cod = acetaminophen + caffeine + butalbital + codeine). Members of the opiate family are the most commonly partnered class (67%). Caffeine, a natural product stimulant seen in four combinations, enhances acetaminophen’s analgesic effects as well as absorption.15 Furthermore, it has been shown that caffeine and aspirin in combination with acetaminophen is more efficacious and has a faster onset of action compared to ibuprofen in the treatment of migraines.16 A faster onset of action as well as a longer duration with tramadol and acetaminophen combination (compared to the individual drugs) has led to its effective use in the management of postoperative pain.17 Morphinan members (codeine, hydrocodone, oxycodone and dihydrocodeine) as well as other opioids (tramadol, pentazocine and dextropropoxyphene) are used as additional analgesics. Clemastine and dexbrompheniramine, both first generation antihistamines, as well as pseudoephedrine, a nasal decongestant, are seen in a few combinations. Approved in 1958, synalgos-DC-A (dihydrocodeine + acetaminophen + caffeine), became the first acetaminophen-containing combination drug available. However, it has since been discontinued along with others. Twenty-six years later butalbital, a barbiturate, was approved in combination with caffeine (fioricet). It is now seen in three combinations with acetaminophen. Percocet, originally approved in 1999, contains oxycodone as the additional component. Although widely used, acetaminophen is amongst the most dangerous and controversial drugs in the world, with a history of false assumptions and errors when initially developed. As of 2011, acetaminophen dosage is limited to 325 mg in all combination drugs. This is because acetaminophen is metabolized to a highly electrophilic species N-acetyl-p-benzoquinone imine (NAPQI), which is a major source of toxicity that can cause acute liver failure (ALF), kidney damage and impaired fetal development.18 Interestingly, research suggests that combination analgesics may induce rebound headaches while losing initial ACS Paragon Plus Environment


Page 16 of 135

anti-headache activity.19 Vicodin, (acetaminophen + hydrocodone) first available in 1983, is used as a narcotic and an analgesic.

Figure 8. Combination Structure Relationship Diagram for Acetaminophen Aspirin Combinations: Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) first introduced in 1899 by Bayer.20,21 Aspirin is indicated both by itself as well as in combination with other drugs as a pain reliever and for anti-inflammatory purposes. However, aspirin also possesses anti-platelet blood thinning properties; this allows it to be used for treatment of various cardiovascular issues in combination with other drugs.22 The combination structure relationship diagram for aspirin is shown in Figure 9. Aspirin has been approved as part of 20 combinations, out of which 19 are structurally unique. Eighteen (90%) of these combinations are approved for nervous system conditions with aggrenox and yosprala being approved for blood and blood forming organ and cardiovascular ACS Paragon Plus Environment

Page 17 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


conditions respectively. Aspirin combinations have been approved continuously since the 1950s, with two to four new combinations approved each decade until the present. Aspirin has been combined with diverse families of structures such as opioids (oxycodone, codeine, dihydrocodeine, propoxyphene and pentazocine) a stimulant (caffeine), muscle relaxants of the carbamate class (carisoprodol, methocarbamol and meprobamate), an analgesic (acetaminophen), a vasodilator (dipyridamole), a proton pump inhibitor (omeprazole), an antihistamine (orphenadrine) and a statin (pravastatin). In 1950, percodan (oxycodone + aspirin) became the first combination drug containing aspirin to be approved. Synalgos- DC (dihydrocodeine + aspirin + caffeine), fiorinal w/cod (aspirin + butalbital + codeine), Soma c/cod (codeine + carisoprodol + aspirin) and excedrin (aspirin + acetaminophen + caffeine), approved in 1983, 1990, 1996 and 2003 respectively, are used as pain relievers especially for headaches. Aggrenox (aspirin + dipyridamole), approved in 1999, helps reduce the risk of stroke in patients with past blood clotting issues. In 2016, yosprala (aspirin + omeprazole) became the most recent aspirin combination to be approved. Yosprala is a platelet aggregation inhibitor used to prevent cardiovascular events in patients at risk of aspirin-induced gastric ulcers.23 Yosprala is the only aspirin combination approved for more than one disease category. It is worth noting that close to half (45%) of these aspirin combinations have been discontinued.



Figure 9. Combination Structure Relationship Diagram for Aspirin ACS Paragon Plus Environment

Page 18 of 135

Page 19 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Metformin Combinations: Metformin, the structure relationship diagram of which can be found in Figure 10, is an anti-diabetic drug indicated for treatment of type 2 diabetes by suppressing liver glucose production.24 First discovered in 1922, metformin traces its roots from Galega officinalis, a plant rich in guanidine shown to lower blood glucose. Along with other guanidine derivatives (biguanides), metformin had a renaissance in the 1940s during a search for antimalarial agents. Although pursued as a treatment for diabetes in 1957, metformin was less potent then phenformin and buformin and therefore received less interest. However, after phenformin and buformin were discontinued in the 1970s due to increased risk of lactic acidosis, metformin finally received some traction and was introduced to the United States market in 1995.25 Furthermore, metformin’s prominence in combination drugs in the treatment of type II diabetes is likely the result of a positive impact on cardiovascular health. Death from cardiovascular disease continues to be a major concern for type 2 diabetes patients.26 Metformin has been approved as a component of fourteen unique combination drugs, out of which four (actoplus MET, avandamet, metaglip and segluromet) have been approved for additional disease categories. A total of five unique structural classes and 2 disease categories (endocrine and metabolism) are represented. All these combinations partner metformin with one other small molecule component. In 1999, amaryl (glimepiride + metformin), became the first metformin-containing combination drug to be approved. In 2017, segluromet (ertugliflozin + metformin), was the latest metformin-containing combination to be approved. The other structural component of every combination is from a different class of antidiabetic drugs in all cases. Four major classes of antidiabetic drugs have been combined with metformin: the gliptins, glitazones, sulfonylureas, and gliflozins.27 The glitazones (pioglitazone and rosiglitazone), recognizable by their thiazolidinedione heterocycle, are seen in two formulations. The gliptins (sitagliptin, saxagliptin, linagliptin and alogliptin) as a class are dipeptidyl-peptidase (DPP)-4 inhibitors; they are seen in four combinations with sitagliptin being the first to be approved as a combination with metformin. Members from the sulfonylurea family (glimepiride, glipizide and glyburide) are found in three combinations, while the gliflozin family (canagliflozin, dapagliflozin, empagliflozin and ertugliflozin) which contain a characteristic pyranose, is represented in four combinations. Finally, the meglitinides (repaglinide) appear in a single metformin combination. Improved glycemic control as well as ACS Paragon Plus Environment


Page 20 of 135

reductions in pills taken and undesirable side-effects are amongst the beneficial reasons cited for metformin combinations.28 For example, weight gain is associated with sulfonylureas and glitazones.29 The addition of metformin can help minimize this weight gain as a result of its ability to increase glucagon-like peptide-1 levels.30,31

Figure 10. Combination Structure Relationship Diagram for Metformin Ethinyl Estradiol Combinations: Contraceptive pills have been on the market for over half a century. It is estimated that over 100 million women are on some regiment of hormonal medication. In the early 1950s, Carl Djerassi synthesized the first oral ACS Paragon Plus Environment

Page 21 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


contraceptive norethindrone, a progestin. Less than a decade later, enovid (norethynodrel + mestranol) became the first contraceptive combination pill to be approved by the FDA.32 The combination structure relationship diagram for ethinyl estradiol is depicted in Figure 11. Ethinyl estradiol, originally approved in 1943, has been approved as component of fifteen combinations of which eleven are structurally unique. All these combinations belong to endocrine and genito-urinary and sex hormone disease categories. Ethinyl estradiol is an estrogen used in birth control as an oral contraceptive.33 Ethinyl estradiol is a synthetic derivative of estradiol, with the only difference between the two being an ethynyl substitution at C17 in the former. This substitution at C17 from the native estrogen secondary alcohol to a tertiary propargylic alcohol is critical as it increases the bioavailability of the drug by slowing the metabolic oxidation of the hydroxyl group at C17 to a ketone. As a result, ethinyl estradiol is several-hundred times more potent in comparison to estradiol.34 Synthetic progestogens are used in conjunction with ethinyl estradiol in all combinations. Beyaz (ethinyl estradiol + drospirenone + levomelate) is the only approved ethinyl estradiol combination with more than two small molecule components. Beyaz contains levomefolate, which is the biologically active form of vitamin B9 (folate). Majority of synthetic progestogens also contain an ethynyl substitution at C17, with exception of drospirenone (a component of beyaz and yasmin) which is substituted with a gamma-spirolactone at the C17 junction. These combinations are used as oral contraceptives for birth control. In 1970, demulen (ethinyl estradiol + ethynodiol diacetate) became the earliest ethinyl estradiol combination to be approved by the US FDA. Xulane (ethinyl estradiol + norelgestromin) is the most recent (2014) ethinyl estradiol combination to receive approval.



Page 22 of 135

Figure 11. Combination Structure Relationship Diagram for Ethinyl Estradiol Lamivudine Combinations: Lamivudine, approved as a monotherapy in 1995, has been used in a variety of combinations for treatment and prevention of HIV-1/AIDS. Lamivudine is an analogue of cytidine with a 1,3-oxathiolane in place of a furanose ring. Like other nucleotide analogues, lamivudine is a nucleoside reverse transcriptase inhibitor which functions by inhibiting both HIV reverse transcriptase. However, in addition, lamivudine is also an inhibitor of hepatitis B virus polymerase.35 As depicted in the combination structure relationship diagram in Figure 12, these fourteen unique combinations are all anti-infective agents, which are represented by six chemical structure ACS Paragon Plus Environment

Page 23 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


categories including peptidomimetic HIV-1 protease inhibitors (atazanavir and ritonavir), nucleosides as well as other structural diversity. It should be noted that ritonavir is currently used as pharmacokinetic enhancer to help increase the bioavailability of protease inhibitors. This is because ritonavir is a cytochrome P450 (CYP450) 3A4 inhibitor.36 Due to the large structures of the many small molecule components of combination drugs including Lamivudine, an alternative, more compact relationship diagram is presented. In the interest of providing compact, informative diagrams, this format will be repeated as necessary through the remainder of the paper. In 1997, combivir (lamivudine + zidovudine) became the first lamivudine combination drug to be approved. Zidovudine, also a nucleoside reverse transcriptase inhibitor, is particularly intriguing for presence of a rare azido (N3) functional group. Zidovudine, at one time recommended as a first line treatment for HIV-1, has limited beneficial effects when given as a monotherapy due to HIV-1 resistance. A strategy to combat this obstacle of drug resistance is combinational therapy with two or more antiretroviral agents. One such fruitful combination with zidovudine is lamivudine. Zidovudine and lamivudine have been shown to possess a synergetic relationship in vitro. Resistance to one of the drugs sensitizes the reverse transcriptase activity of the other. One such example is viruses with a mutation at codon 184 of the HIV-polymerase gene are resistant to lamivudine, but not zidovudine.37 In 2018, symfi Lo (lamivudine + efavirenz + tenofovir disoproxil) and delstrigo (doravirine + lamivudine + tenofovir disoproxil fumarate) became the latest lamivudine combinations to be approved for treatment of HIV-1. To date, lamivudine has been combined with HIV protease inhibitors (ritonavir, atazanavir), HIV integrase strand transfer inhibitors (dolutegravir and raltegravir), other nucleoside analog reverse-transcriptase inhibitors (abacavir, stavudine and zidovudine), non-nucleoside reverse transcriptase inhibitor (efavirenz, nevirapine and doravirine), as well as a nucleotide reverse transcriptase inhibitor (tenofovir disoproxil). In the interest of finding effective cost-effective drug reduction strategies, there continues to be contemporary research investigating the role of utilizing a pharmacokinetic (PK) booster such as ritonavir in combination with a dual therapy such as lamivudine + atazanavir.38



Page 24 of 135

Figure 12. Combination Structure Relationship Diagram for Lamivudine Emtricitabine Combinations: Emtricitabine, an analogue of cytidine and an antiretroviral drug of the reverse-transcriptase inhibitor class, is used for both the prevention and treatment of HIV-1.39 A fluorine atom at C5 and an oxathiolane in place ACS Paragon Plus Environment

Page 25 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


of a dihydroxyfuran distinguishes this drug structurally from cytidine. A single fluorine atom distinguishes emtricitabine from lamivudine. Emtricitabine has both a higher bioavailability (93% vs 86%) as well as serum half-life (10 h vs 5-7 h) compared to lamivudine.40 It has been approved as a component of nine combination drugs to combat HIV-1, which are displayed in Figure 13. Interestingly, these nine combinations are only represented by eight unique chemical partners which have been combined as combinations of two (22%), three (56%) or four (22%) components respectively. Overall, six unique structural classes of drugs and one disease category (anti-infective) are represented. Either tenofovir alafenamide or tenofovir disoproxil, both reverse transcriptase inhibitor adenine analogues, are seen in every combination. Integrase inhibitors (elvitegravir and bictegravir), which function by preventing integrase from delivering viral genome information to the DNA of the host cell, appear in three combinations.41,42 Cobicistat, a pharmacokinetic enhancer that functions by inhibiting CYP450 (CYP3A) enzymes, is a component of two combinations.43 Non-nucleoside reverse transcriptase inhibitors (efavirenz, rilpivirine and nevirapine) turn up in four combinations. Emtricitabine combinations are relatively recent with, Truvada (emtricitabine + tenofovir disoproxil) became the first combination to be approved in 2004. In the last fourteen years, eight additional emtricitabine combinations have been approved. Biktarvy (emtricitabine + tenofovir alafenamide + bictegravir), which treats chronic HIV-1 infection in patients who have no current antiretroviral treatment program, was the latest emtricitabine combination drug to be approved in 2018.



Page 26 of 135

Figure 13. Combination Structure Relationship Diagram for Emtricitabine Amlodipine Combinations: Amlodipine is a long-acting 3rd generation dihydropyridine (DHP) calcium channel blocker originally approved in 1981 to treat hypertension and angina.44 Amlodipine contains a 1,4-DHP central core, which is characteristic of many other calcium channel blockers. The central DHP cores are synthesized using the classic Hantzsch reaction, known since 1882. Like all other DHP blockers, a phenyl substituent at C4 is crucial for antagonist activity. The structure relationship diagram for amlodipine’s ten US FDA approved combinations is ACS Paragon Plus Environment

Page 27 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


presented in Figure 14. These combinations are represented by five structural classes and all are approved to treat cardiovascular conditions. For example, caduet combines amlodipine with atorvastatin, a member of the statin family, to reduce cardiovascular events. Amlodipine is also seen in combinations with ACE inhibitors (benazepril and perindopril), angiotensin-II receptor antagonists (olmesartan, valsartan and telmisartan), a diuretic (hydrochlorothiazide), and a renin inhibitor (aliskiren). In 1995, lotrel (amlodipine + benzapril) became the first amlodipine-containing combination to be approved. In 2010, the latest year when amplodipine combinations were approved, tekamlo (aliskiren + amlodipine), amturnide (aliskiren + hydrochlorothiazide + amlodipine) and tribenzor (olmesartan medoxomil + hydrochlorothiazide + amlodipine) were approved. Olmesartan medoxomil is a prodrug of olmesartan; the 1,3-dioxol-2-one moiety enhances the bioavailability of the parent drug as it is metabolized to the free acid in vivo.45 Benazepril and perindopril are also ester prodrugs, metabolized in the liver to benazeprilat and perindoprilatin respectively.46



Page 28 of 135

Figure 14. Combination Structure Relationship Diagram for Amlodipine Neomycin Combinations: Neomycin, an aminoglycoside discovered in 1949, is used as an antibiotic in combination with a variety of other structures.47 Neomycin is effective against most gram-negative bacteria, and although it is active against ACS Paragon Plus Environment

Page 29 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


staphylococci, it is not effective against all gram-positive bacteria. Thus, in order to attain a broader spectrum of antibacterial activity, some neomycin combinations contain additional antibiotics which are more effective against gram-positive bacteria. Neomycin’s combination structure relationship diagram is depicted in Figure 15. A total of 24 combinations containing neomycin have been approved, out of which 19 are structurally unique. All but two (lidocaine and thonzonium) of neomycin’s combination partners are either steroid derivatives or natural product macrocyclic peptides. The primary indications for these combination is anti-infective; however some of these combinations target sensory organ and/or dermatological areas.48 The majority (58%) of neomycincontaining combinations drugs were approved in the 1960s. Polymyxin B, a lipopeptide macrolactam antibiotic effective against gram negative bacterial infections, is neomycin’s most frequent combination partner and is found in a total of eleven (46%) combinations.49 The polymyxin b + neomycin combinations were designed to be full spectrum antibiotics effective against both gram-negative and gram-positive bacteria; polymyxin b is only effective against gram negative bacteria. Bacitracin, which appears in five combinations, is a cyclic peptide isolated in 1945 solely effective against gram-positive bacteria.50 Bacitracin combined with neomycin is effective against both gram-positive and gram-negative bacteria.51 Gramicidin, which is part of one combination (Neosporin) approved for two disease categories, is a cyclic peptide isolated in 1939 as a mixture of three compounds. Gramicidin is an antibiotic mostly effective against gram-positive and select gram-negative.52,53 Colistin, an antibiotic produced from paenibacillus polymyxa, is a polymyxin polypeptide antibiotic effective against most gram-negative bacteria.54 The steroidal components (hydrocortisone, dexamethasone, fluocinolone acetonide, prednisolone acetate, methylprednisolone, triamcinolone acetonide and flurandrenolide) of these combinations act as anti-inflammatory agents. Lidocaine, a local anesthetic, and thonzonium bromide, a surfactant, are seen in one and two combinations, respectively. The primary indication for these combinations is anti-infective with the additional agents added to relieve inflammation. In 1957, cortisporin, which is a mixture of the four components hydrocortisone, neomycin, polymyxin b, and bacitracin, was the earliest neomycincontaining combination drug to be approved. Cortisporin is used to treat swimmer’s ear, an infection of the outer ear. It is still currently available. In 1987, neosporin G. U. (neomycin + polymyxin B) became the most recent neomycin combination to be approved as antibiotic cream to treat infections. Neosporin continues to be a popular ACS Paragon Plus Environment


Page 30 of 135

household item. The majority of neomycin combinations were approved in the 1960s (a total of 14). Maxitrol (dexamethasone + neomycin + polymyxin b), approved in 1963, is used as an ophthalmic anti-bacterial agent. Dexamethasone, the steroid component, controls the inflammation. Neo-Synalar (fluocinolone acetonide + neomycin), approved in 1963, combines an anti-infective with a steroid. Neomycin acts as the anti-infective against bacteria such as S. aureus; fluocinolone acetonide is added to treat mild to moderate dermatitis while additionally reducing itching and inflammation.


Page 31 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



Page 32 of 135

Figure 15. Combination Structure Relationship Diagram for Neomycin

Introduction to disease categories In the following eleven sections we present all the structures approved as part of US FDA combinations. To make this extensive small-molecule dataset more accessible, we have chosen to break it down according to the disease category for which these small molecule structures were approved as combination drug components. We concluded that this organizational strategy would be most attractive and useful to researchers interested in chemical architectures that have made it all the way to approval for any given disease category. To better aid the reader, structures that share common cores are graphically summarized as one structure with colored circles employed to highlight differences. This display approach reveals that many drugs are quite similar too each other, which is especially evident for steroids, morphinan members, and antibiotics. Furthermore, we have separated the small molecule structures within each disease category into two components: primary or secondary. “Primary” components, labeled in a pink color, indicate that these drugs directly treat a medical condition associated with the disease category. “Secondary” components, labeled in blue, indicate that these drugs are added to the primary component as additives to control side effects, or because they are primary components for treating a different disease category, but target regions of the body associated with the secondary disease category. For example, urinary and respiratory infections are treated with antibiotics, which are anti-infectives. Therefore, these antibiotics appear as primary components in the anti-infective disease category; however, these drugs also appear as secondary components in the genito-urinary and respiratory disease categories because they also target urinary and respiratory regions of the body.

Anti-Infectives US FDA approved anti-infective drug combination components are displayed in figures 16A and 16B. We have broken the discussion of these 79 molecules, which make up 74 approved combinations, into two sections. The first section is focused on antivirals (Figure 16A and B) while the second section is dedicated to coverage of antibiotics and miscellaneous anti-infectives. These combinations are utilized in a variety of ways, such as broadspectrum antibiotics, antivirals against HIV-1 and hepatitis C, tuberculosis, topical steroid and nonsteroidal antiACS Paragon Plus Environment

Page 33 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


infectives. Remarkable structural diversity is represented in this second largest of the combination drug families, including natural product antibiotics, beta-lactams, nucleoside derivatives and antiviral peptides. Section 1 (antivirals): The heavy hitters in this category are the nucleoside drugs lamivudine, emtricitabine and tenofovir disoproxil, which are all in the list of top 24 drugs, having been approved as part of fifteen, nine and nine anti-infective combinations respectively. These three drugs are all components of combinations used to treat HIV-1/AIDS. Lamivudine and emtricitabine are differentiated by a single point of substitution on the nucleobase (H vs F). Other classes of antivirals are almost exclusively seen in combinations with lamivudine or emtricitabine and are all indicated for treatment of HIV-1. One such family, the integrase inhibitors (INIs) (-tegravir), are a relatively new family of antivirals seen in antiviral combinations. The INIs are recognizable by a pyridin-4(1H)-one or related heterocycle as well as various less-common heterocycles such as oxadiazole, 1,3oxazepane, 1,3-oxazinane. A more comprehensive discussion on specific classes antiviral drugs, seen in combinations for HIV-1 treatment, were previously discussed in the lamivudine and emtricitabine sections above. A myriad of combinations to treat hepatitis C have been approved. Three protease inhibitors (NS5A, NS5B and NS3/4A) in the hepatitis C virus are targeted in seven unique combinations. In 2014, harvoni (ledipasvir + sofosbuvir) and viekira pak (dasabuvir + ombitasvir + paritaprevir + ritonavir) became the earliest hepatitis C combinations to be approved. Structurally, many of the antiviral families share common recognizable motifs. NS5A inhibitors (-asvir) contain a center heterocycle or aromatic that is heavily flanked on both sides by nitrogen heterocycles (usually imidazoles) and peptide components. These inhibitors are quite large, with two members being centrally symmetrical (ombitasvir and pibrentastvir). NS3/4A protease inhibitors (-previr) are strikingly similarly looking macrolactams decorated with two or three cyclopropane rings, and a highly decorated hydroxypyrrolidine. In addition, 75% contain a quinoxaline heterocycle. Both NS5B inhibitors (-buvir) contain an uracil nucleotide.



Figure 16A. Anti-Infective (Anti-HIV) Approved Primary Combination Structures


Page 34 of 135

Page 35 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 16B. Anti-Infective (Antiviral) Approved Primary Combination Structures Section 2 (antibiotics and various anti-infectives): The most notable members of this category are polymyxin B, neomycin, hydrocortisone acetate and hydrocortisone, all of which appear in the top 24, having been approved as


Page 36 of 135

parts of ten, seven, five and four combination drugs respectively. Sulfonamides (sulfacetamide and sulfisoxazole acetyl), natural products (gentamicin, tobramycin, polymyxin B, oxytetracycline and erythromycin), a folate synthesis inhibitor (trimethoprim), and a fluoroquinolone (ciprofloxacin) represent the diverse types of antibiotic families seen in anti-infective combinations. Corticosteroids are frequently used in combinations with antiinfectives as secondary components in controlling inflammation. In 1953, chloromycetin hydrocortisone (chloramphenicol + hydrocortisone acetate) became the earliest anti-infective combination to be approved. Bactrim (trimethoprim + sulfamethoxazole), approved in 1973, is utilized as a broad-spectrum antibiotic. Trimethoprim, a trisubstituted pyrimidine, has been used as an antibiotic, usually against bladder infections. Sulfamethoxazole, an isoxazole sulfonamide, is utilized as a broad-spectrum antibiotic and to treat bladder infections, bronchitis and prostatitis. Bactrim is a historically significant combination drug, as it was the first combination to be approved under the FDA’s new stringent guidelines which required evidence that a combination offered “a therapeutic advantage over each of the components administered separately”.55 The carbapenems, penams, oxapenams cephalosporins, and all other members of the beta-lactam family are usually combined with beta-lactamase inhibitors to help extend their activity and prevent degradation. In 1985, primaxin (imipenem + cilastatin)39 became the earliest combination to contain a -lactam antibiotic and a -lactamase inhibitor. Cilastatin is a renal dehydropeptidase inhibitor which helps prevent host modification of -lactam antibiotics.56 Unasyn (ampicillin + sulbactam), zosyn (piperacillin + tazobactam), augmentin (amoxicillin + clavulanate) and augmentin XR (amoxicillin + clavulanate) approved in 1986, 1993, 1996 and 2002 respectively, are broad-spectrum beta-lactam antibiotics effective against a variety of bacterial infections. Common respiratory infections, such as bronchitis, pneumonia, sinusitis, are treated using a beta-lactam antibiotic and beta-lactamase inhibitors. Rifamate (isoniazid + rifampin) and rifater (isoniazid + pyrazinamide + rifampin) approved in 1975 and 1994 respectively, are both indicated for pulmonary tuberculous. Rifampin is a member of the rifamycin family of antibiotics. Peroxidative activation of isoniazid by mycobacterial enzyme KatG generates a reactive species which then covalently binds to nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) (both nucleic acid and lipid enzyme inhibitors).57 Recently, non-β-lactam βlactamase inhibitors (avibactam and vaborbactam) have been used in conjunction with a -lactams as broadACS Paragon Plus Environment

Page 37 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


spectrum antibiotics.58,59 Urinary tract infections are treated with a cephalosporin beta-lactams (ceftolozane or ceftazidime) in combination with a beta-lactamase inhibitors (avibactam or tazobactam). Avibactam is unique among these structures as it doesn’t contain a beta-lactam. In fact, it is a founding member of the diazabicyclooctanes (DBOs), a new class of non-β-lactam β-lactamase inhibitors effective against class A and C β-lactamases. The hypothesis that DBOs could be potential β-lactam mimics was proposed by chemists at Hoechst Marion Roussel (HMR) in the mid-1990s. HMR eventually merged with Rhone-Poulenc and Sanofi to form Sanofi-Aventis. When Sanofi-Aventis decided to drop their anti-infective program, the DBO project was inherited by a spin-off company, Novexel. Progress finally was made after Novexel was acquired by Astra-Zeneca; avibactam was released shortly after. DBOs have yet to reach their potential, as lengthy syntheses are required to produce these unique compounds.60 Unlike traditional β-lactamase inhibitors whose mechanism of action is through irreversible covalent inhibition, avibactam operates as a reversible covalent inhibitor. This reversible covalent inhibition aids in protecting avibactam’s β-lactam combination partners from hydrolysis.61 Vaborbactam contains a structurally unique oxaborinanol heterocycle. Boron-containing drugs are an emerging class of pharmaceuticals. Boron possesses unique properties that can be exploited in tuning a drug’s mechanism of action to target specific diseases.62 For example, boronic acids are also unique in that they can function as transition state analogs with serine residues as result of their ability to reversibly form covalent bonds with alcohols. This allows them to be effective inhibitors of serine carbapenemase. This is precisely why vaborbactam is thought to be a strong inhibitor of various β-lactamases.63 Synercid (quinupristin + dalfopristin), approved in 1999, is used to treat bacterial infections resistant to other antibiotics such as vancomycin. Both quinupristin and dalfopristin are pristinamycin derivatives of the streptogramin antibiotic class. This combination treats enterococcus faecium previously resistant to vancomycin and staphylococcus.64 Pyocidin (polymyxin B + hydrocortisone) and otovel (ciprofloxacine + fluocinolone acetonide) were both approved in 2016 for the treatment of acute otitis media. One hydroxyquinoline member (clioquinol) appears in combination with nystatin (nystaform). Clioquinol is structurally notable as it contains two different halogen atoms (chlorine and iodine). The hydroxyquinoline family is thought to possess diverse bioactivity (anti-neurodegenerative, anti-cancer, antifungal, antioxidative, antimicrobial, antidiabetic etc.) as result of their ability to chelate metals such as Zn, Fe, and Cu.65 ACS Paragon Plus Environment



Page 38 of 135

Page 39 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 17A. Anti-Infective (Non-viral) Approved Primary Combination Structures

Figure 17B. Anti-Infective (Non-viral) Approved Secondary Combination Structures

Alimentary Tract and Metabolism All 52 structures, which are part of 31 US FDA approved alimentary tract and metabolism combinations, are presented in Figure 18A and 18B. Metformin is the only drug in this category that is in the list of top 24 most commonly utilized combination drug components. Out of 31 combination drugs approved for treatment of alimentary tract and metabolism related conditions, six include Metformin as a contributing INN. Metformin was first partnered with pioglitazone in 2000 followed by rosiglitazone, alogliptin, empagliflozin, ertugliflozin and most recently glipizide in 2008. In 1960, lomotil (diphenoxylate + atropine), was approved as an antidiarrheal making it one of the earliest alimentary tract combinations to be approved. Diphenoxylate, an opioid member of the phenyl piperidine class, acts as the antidiarrheal. Atropine, an anticholinergic, is included in this combination ACS Paragon Plus Environment


Page 40 of 135

to discourage overdose with an opioid. If too much Lomotil is taken, atropine will cause undesirable side effects such as nausea.66 The prazole proton pump inhibitors (esomeprazole, omeprazole, and lansoprazole), recognizable by their benzimidazole core, are parts of combinations with common NSAID’s to treat arthritis and cardiovascular events in patients at risk of gastric ulcers. Prazoles have also been combined with natural product antibiotics and penams to treat gastric ulcers caused by H. pylori. In 1999, prevpac (lansoprazole + amoxicillin + clarithromycin) became the first approved combination drug containing a prazole. Famotidine, an H2 antagonist recognizable by its thiazole, thioether and guanidine, as well as misoprostol (a prostaglandin analogue) appear in combinations with an NSAID’s as well to treat gastric ulcers. Ammonul (sodium phenylacetate + sodium benzoate), approved in 1960, is indicated for acute hyperammonemia and encephalopathy associated with deficient urea cycles. This combination helps patients eliminate nitrogen through an alternate mechanism.67 Contrave (bupropion + naltrexone), approved in 2014, is used for weight loss.68 Bupropion, a substituted cathinone antidepressant of the norepinephrine-dopamine reuptake inhibitor (NDRI) family, and naltrexone, an oxymorphone analogue which manages opioid dependence, help the brain regulate appetite. Lonsurf (trifluridine + tipiracil), approved in 2015, is a combination used to treat metastatic colorectal cancer. Its components are trifluridine, a nucleoside analogue, and tipiracil, a thymidine phosphorylase inhibitor. Four major classes of antidiabetic drugs are components of alimentary tract and metabolism combinations: the gliptins, glitazones, sulfonylureas, and gliflozins.15 Duetact (pioglitazone + glimepiride), oseni (alogliptin + pioglitazone), glyxambi (empagliflozin + linagliptin), steglujan (ertugliflozin + sitagliptin), and qtern (dapagliflozin + saxagliptin), approved in 2006, 2013, 2015, 2017 and 2017 respectively, also treat type 2 diabetes. Because the pathogenesis of type 2 diabetes is usually caused by multiple defects, combining two anti-diabetic drugs with distinct mechanisms of actions has been shown to be an effective route to treating type 2 diabetes. For example, the thiazolidinediones (TZDs) such as pioglitazone, facilitate the uptake of peripheral glucose while (DPP)-4 inhibitors such as alogliptin enhance insulin secretion from the pancreas. These complementary modes of action can lead to a more efficacious treatment for the patient.69


Page 41 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 18A. All Alimentary Tract and Metabolism Approved Primary Combination Structures


Figure 18B. All Alimentary Tract and Metabolism Approved Secondary Combination Structures


Page 42 of 135

Page 43 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Cardiovascular The 57 molecular components of all 64 US FDA-approved cardiovascular drug combinations are depicted in Figure 19 A and 19B. These drugs are primarily used to treat hypertension and high cholesterol. Cardiovascular combinations are the third most frequent disease category, with cardiovascular combination drugs having been continuously approved since the 1950s to the present day. This category contains hydrochlorothiazide, which is the most commonly combined drug component found in 35 combinations, of which 33 are used to treat cardiovascular conditions. Amlodipine is the second most frequently partnered cardiovascular component, appearing in ten approved cardiovascular combinations. Approved in 1958, Diupres-250 (reserpine + chlorothiazide), is the first cardiovascular combination to be approved. Enduronyl (deserpidine + methyclothiazide) and dralserp (hydralazine + reserpine), approved in 1961 and 1977 respectively, are examples of reserpine type family compounds used to treat hypertension. Reserpine is a natural product alkaloid with antipsychotic and anti-hypertensive properties. It has a structure identical in most respects to deserpidine with exception of a methoxy ether group present on the indole ring of reserpine. There has been much debate over why hydrochlorothiazide has been preferred over chlorthalidone both in monotherapy as well as combination drugs. Although hydrochlorothiazide is seen in most combinations, chlorthalidone, a thiazide-like diuretic, possesses a very similar pharmacological profile, with some concluding chlorthalidone is superior.70,71,72 Despite this, chlorthalidone is only seen in six combinations: Regroton (chlorthalidone + reserpine),k (chlorthalidone + betaxolol), lopressidone (chlorthalidone + metoprolol), tenoretic (atenolol + chlorthalidone), clorpres (clonidine + chlorthalidone) and edarbyclor (chlorthalidone + azilsartan medoxomil). One intriguing explanation for hydrochlorothiazide’s preference over chlorthalidone is because hydrochlorothiazide’s abbreviation (HCT when used in a combination drug) lends itself for easier prescription writing over chlorthalidone.73 Amiloride, is unique in that it is structurally distinct from other diuretics as it contains a pyrazine-carbonyl-guanidine. Unlike the thiazides which interfere with the Na-Cl antiporter, amiloride is a epithelial sodium channel blocker.74 The angiotensin II receptor antagonists (sartan family) are heavily represented in this catagory. This family is easily recognizable as most members contain characteristic tetrazole, biphenyl-methyl and imidazole pharmacophores. Tetrazoles can function as carboxylate group bio-isosteres.75 In 1995, hyzaar (losartan + hydrochlorothiazide) ACS Paragon Plus Environment


Page 44 of 135

became the first combination containing a sartan member to be approved. Various beta blockers are also seen in combinations with cardiovascular drugs and diuretics. These members contain a characteristic aminopropanol component attached to an aromatic group. Three generations of beta blockers exist. The first generations were nonselective and predominately ortho-substituted on their aromatic ring. However, the selectivity of beta-blockers was not realized until para-substituted aromatics displayed 1 selectivity. In 1979, inderide (propranolol + hydrochlorothiazide) became the earliest combination to contain a beta-blocker to be approved. In 2016, byvalson (nebivolol + valsartan) became the most recently approved beta-blocker combination. Nebivolol, a thirdgeneration beta-blocker, is structurally a dimer which is unique for this family. Verapamil is the sole representative of the phenylalkylamine family of calcium channel blockers. It was among the earliest compounds identified to block Ca2+ in the early 1960s.76 Verapamil also has the distinction of being the only calcium channel blocker to be indicated for all three variants of angina (vasospastic, chronic stable and unstable).77,78 In 1996, verapamil was approved as a combination (tarka) with the ACE inhibitor trandolapril to treat hypertension. The DHP family of calcium channel blockers (amlodipine and felodipine) are also represented in antihypertensive combinations. In 1999, Aggrenox (aspirin + dipyridamole), was approved to combat stroke. Dipyridamole, a platelet inhibitor, contains an intriguing fused dipyrimidine heterocycle. Dicurin Procaine (procaine + merethoxylline + theophylline) combines a procaine (local anesthetic) with theophylline (xanthine bronchodilator) and is used as a diuretic. Theophylline, along with natural methylxanthines, was once used as a diuretic before more potent diuretics became available.79 Mercurial diuretics, such as merethoxylline were once very commonly used. They have widely been replaced by safer diuretic alternatives such as thiazides. Procaine limits the discomfort of merethoxylline when it is injected into the tissues.


Page 45 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 19A. All Cardiovascular Approved Primary Combination Structures


Figure 19B. All Cardiovascular Approved Antihypertensive and Secondary Combination Structures


Page 46 of 135

Page 47 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Dermatological All 24 combination components of the 21 US FDA approved dermatological combination drugs are shown in Figure 20. Survey of these structures quickly reveals that natural products and their derivatives play a major role (78%). Most prominent among those are steroids (30%), with representation also from complex macrocycles, carbohydrates, vitamin derivatives and other natural motifs. Most notable among these structures is neomycin, the #2 ranked compound seen in combinations, which has been approved as part of eleven dermatological combinations. Neomycin is frequently seen in combinations with corticosteroids. This is because patients diagnosed with atopic dermatitis are often predisposed to secondary bacterial infections. The atopic dermatitis is treated with fluocinolone acetonide as the primary indication which also controls inflammation; neomycin is added as the anti-bacterial agent.80 Polymyxin B, hydrocortisone, and hydrocortisone acetate, all of which are in the list of top 24 combination drug components, have been approved for three, three, and two dermatological drug combinations respectively. Indications range from acne, athlete’s foot, melisma and plaque psoriasis. In 1954, Achromycin (procaine + tetracycline) became the earliest dermatological combination to be approved. Tetracyclines have been used by dermatologists to treat acne vulgaris for decades.81 Epifoam (hydrocortisone + pramoxine), approved in 1979, is used as an antipruritic. Pramoxine, a synthetic morpholine-containing topical anesthetic, prevents the itching while hydrocortisone, a naturally occurring steroid, acts as an anti-inflammatory agent. Lotrisone (clotrimazole + betamethasone), approved in 1984, is a topical antifungal agent used to treat conditions such as athlete’s foot and ringworm. Clotrimazole, a synthetic imidazole of the azole antimycotic family, acts as the antifungal component82 while betamethasone, a synthetic steroid, controls the inflammation. Benzamycin (erythromycin + benzoyl peroxide), duac (benzoyl peroxide + clindamycin), ziana (clindamycin + tretinoin), and epiduo (adapalene + benzoyl peroxide), approved in 2000, 2002, 2006 and 2008 respectively, are approved to treat acne. Benzoyl peroxide has been used to reduce Propionibacterium acnes as well as inflammation associated caused by acne for decades. Contrary to most antibiotics, benzoyl peroxide is directly toxic to P. acnes, therefore no drug related resistance is seen. In addition, benzoyl peroxide helps prevent the emergence of erythromycin and clindamycin resistant P. acnes strains when used in combination.83 Tri-Luma (fluocinolone acetonide + hydroquinone + tretinoin), approved in 2002, is a skin bleaching agent used to treat ACS Paragon Plus Environment


Page 48 of 135

melisma. Fluocinolone acetonide (a corticosteroid) acts as an anti-inflammatory agent; tretinoin, (a retinoid) acts as a skin exfoliant; and hydroquinone acts as a melanin synthesis inhibitor, lightening the skin by inhibiting melanin.84 Taclonex (calcipotriol + betamethasone dipropionate), approved in 2008, is indicated for treatment of plaque psoriasis. Calcipotriol, a vitamin D3 analog, helps slow the growth of skin cells while betamethasone dipropionate, a corticosteroid, controls the inflammation.85 Adapalene, a vitamin A derivative (retinoid) indicated for treatment of acne, contains an adamantane. The route of administration of dermatological combinations are primarily topical and cutaneous, as most are formulated as creams, gels or aerosols.


Page 49 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



Page 50 of 135

Figure 20. All Dermatological Approved Combination Structures

Endocrine System All 29 endocrine system combination structure components are shown in Figure 21A and 21B. A total of 26 combinations are used to treat conditions such as type 2 diabetes and menopause. Most commonly utilized among these structures is metformin, which is a component of twelve approved endocrine system combinations. Other top 24 structures which have been approved for this disease category are ethinyl estradiol, conjugated estrogens and hydrochlorothiazide approved for three, three, and two, combinations respectively. Steroids play a significant role as components, as do antidiabetic and cardiovascular drug families. In 1995, prempro and premphase (conjugated estrogens + medroxyprogesterone) became the earliest combination to be approved. Four major classes of antidiabetic drugs appear in endocrine system combinations: the gliptins, glitazones, sulfonylureas, and gliflozins. In a truly unique combination, Qsymia (phentermine + topirimate), approved in 2012, is used for weight loss. Topirimate’s unique structure consists of three oxygen heterocycles. Topirimate is also interesting therapeutically because it is generally used as an anticonvulsant, however, it also possesses weight loss side effects. The role of phentermine, a substituted amphetamine, in this combination is to help suppress appetite. Prempro and premphase (conjugated estrogens + medroxyprogesterone) and duavee (bazedoxifene + conjugated estrogens), approved in 1995 and 2013 respectively, are used to treat menopause symptoms as well as postmenopausal osteoporosis.


Page 51 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 21A. All Endocrine System Approved Primary Combination Structures


Page 52 of 135

Figure 21B. All Endocrine System Approved Secondary Combination Structures

Genito-Urinary and Sex Hormones The 45 genito-urinary and sex hormone drug combination components are displayed in Figure 22A and 22B. A total of 38 unique US FDA approved combinations are used as oral contraceptives, as hormone therapy to treat menopause symptoms, and antibiotics to treat urinary tract infections. Steroid structures do not only represent the majority of all small molecule structures (53%), but they are also the three most utilized components with ethinyl estradiol, conjugated estrogens and norethindrone acetate appearing in twelve, four and four genitourinary and sex hormone combinations respectively. Closer examination reveals four common substitution locations with progestins and three substitution locations with estrogens wherein all structural differences occur among its members. In second place in terms of combination component frequency are beta-lactams (12%). In 1957, PMB 200 (conjugated estrogens + meprobamate) became the first combination to be approved. Lupaneta pack (norethindrone acetate + leuprolide acetate), approved in 2012, treats pain caused by endometriosis. Leuprolide acetate is a synthetic gonadotropin releasing hormone nonapeptide analog. Jalyn (dutasteride + tamsulosin), approved in 2010, treats benign prostatic hyperplasia (BPH) in males. Dutasteride, a 5α-reductase inhibitor, treats the enlarged prostate by inhibiting the formation of dihydrotestosterone (DHT) from testosterone.86 Tamsulosin, an alpha-1 blocker, relaxes bladder neck muscles in the prostate to make it easier to ACS Paragon Plus Environment

Page 53 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


both urinate and pass kidney stones.87 Various progestin and estrogen derivative combinations are used as oral contraceptives as well as to treat menopausal symptoms.88 Diclegis (doxylamine + pyridoxine), reapproved in 2013, treats morning sickness during pregnancy. Doxylamine, a first-generation antihistamine, is employed with pyridoxine, vitamin B6. Diclegis was originally marketed under the name bendectin. Bendectin was originally approved in 1956 with an additional component, dicyclomine.89 However, dicyclomine was removed from the original formulation due to lack of efficacy.90 In 1983, after various controversial lawsuits against bendectin without any scientific evidence to support, the manufacture decided to discontinue the drug. The lawsuits alleged a variety of birth defects such as congenital defects. One lawsuit alleged that bendectin caused unilateral fetal limb reduction, although that is biologically implausible. Shortly after its discontinuation, the impact was immediately noticeable as the number of women admitted to hospitals for vomiting doubled.91



Figure 22A. All Genito-Urinary & Sex Hormones System Approved Primary Combination Structures


Page 54 of 135

Page 55 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 22B. All Genito-Urinary & Sex Hormones System Approved Secondary Combination Structures

Musculo-Skeletal The eighteen musculo-skeletal combination component structures are shown in Figure 23. These eighteen structures appear in ten unique combinations. Natural products and their derivatives play a prominent role in this disease category. Steroids are the major structural family (22%), which also happens to contain the only components (conjugated estrogens and norethindrone acetate) that are in the top 24 and approved for more than one combination (two each). Other notable members include morphinans, NSAIDS and various antacids. Many combinations in this family are used to treat gout, a type of arthritis, which is caused by elevated levels of uric acid in the blood. In 1976, colprobenecid (probenecid + colchicine) became the earliest combination to be ACS Paragon Plus Environment


Page 56 of 135

approved. Probenecid helps facilitate uric acid secretion while its partner colchicine, a natural product, is a nonNSAID anti-inflammatory agent used to control inflammatory arthritis in patients with gout. Another interesting combination that treats hyperuricemia associated with gout involves lesinurad, a URAT1 inhibitor in conjunction with allopurinol, a member of the xanthine family.92 Lesinurad is unique structurally, as it contains a triazole, bromine atom (rare in pharmaceuticals), as well as a cyclopropane which are being seen more frequently. URAT1 is a protein responsible for reabsorbing uric acid in the kidneys. Allopurinol functions by inhibiting xanthine oxidase, an enzyme ultimately responsible for the synthesis of uric acid. Various arthritis conditions are controlled by combining an NSAID (naproxen or ibuprofen) with an antacid (esomeprazole or famotidine). For example, Duexis (ibuprofen + famotidine), approved in 2001, treats symptoms of osteoarthritis or rheumatoid arthritis. Steroid hormone (estrogens, progestins) combinations treat various menopausal symptoms. Bazedoxifene, a thirdgeneration selective estrogen receptor modulator (SERM), helps prevent postmenopausal osteoporosis.93 Targiniq ER combines two morphinan members (oxycodone and naloxone) in its utilization as a pain reliever. Atropine and pralidoxime have been used in combination to treat organophosphate poisoning through countering the acetylcholinesterase inhibitory effects of organophosphates.94 This combination is given as an intramuscular injection.


Page 57 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 23. All Musculo-Skeletal Approved Combination Structures

Nervous System All nervous system combination drug components are shown in Figure 24A and 24B. This is the largest combination drug disease category and has remained one of most frequently approved each decade from the 1940s to the present. Remarkably, ten of the top 24 most commonly utilized combination drug components belong to this category. These notable structures are pseudoephedrine (#3), aspirin (#4), acetaminophen (#5), codeine (#12), hydrocodone (#13), caffeine (#14), ibuprofen (#16), lidocaine (#19), phenylephrine (#20) andchlorpheniramine (#22). The most prominently occurring architectures are highlighted in boxes in Figure 24A and B. For example, ACS Paragon Plus Environment


Page 58 of 135

eleven -morphan members, seven -caines and seven epinephrine types have been used as components of nervous system combinations. The majority of the 78 US FDA approved nervous system combinations are used as pain relievers. Some combinations are local anesthetics, with the majority containing a vasoconstrictor of the catecholamine drug class and an anesthetic. A few of the combinations contain an antidepressant as one component and are indicated for various mood disorders. The remaining combinations are used to treat Parkinson’s and Alzheimer’s symptoms. In 1948, cafergot (ergotamine + caffeine) became the first nervous system combination to be approved. Therapeutically, ergotamine acts as a vasoconstrictor and is used to treat migraines. Interestingly, ergotamine has an affinity for serotonin, dopamine and norepinephrine receptors.95 Treximet (naproxen + sumatriptan) was approved in 2008 for the treatment of migraines and cluster headaches. In 1991, sumatriptan became the earliest member of the triptan family to be introduced. However, due to undesirable pharmacokinetic properties such as low bioavailability and lipophilicity, second generation triptans are more commonly used.96 As a result of sumatriptan’s low lipophilicity, it acts as a peripherally restricted vasodilator.97 Sumatriptan, an analogue of serotonin, acts as an 5HT1b and 5HT1d-receptor agonist constricting cranial blood vessels.98 Advil PM (diphenhydramine + ibuprofen) and Aleve p.m. (diphenhydramine + naproxen), are approved in 2005 and 2014 respectively, as sleep aids. In these combinations, the lipophilic first-generation antihistamine diphenhydramine helps initiate sleep as result of its ability to penetrate the blood brain barrier inducing sedative effects. Pain reliever combinations commonly consist of an opiate (usually morphinan member) partnered with either an NSAID, or another opiate. In 1950, percodan (aspirin + oxycodone) was the earliest NSAID/opiate combination to be approved. Three decades later, Talwin NX (naloxone + pentazocine) became the first opiate/opiate combination to be approved. Opioid dependence, and addiction, has been a serious problem for many years. In 2013, zubsolv (buprenorphine + naloxone) was approved to aid in the treatment of opioid dependence. Both buprenorphine and naloxone are competitive opioid receptor antagonists. Naloxone, a synthetic morphinan derived from oxymorphone, contains an allyl group on N17 of the D piperidine ring while buprenorphine, derived from thebaine, contains a characteristic ethylene bridge at C6-C14 and unique alkyl substitutions at C7 and N17. Local anesthetics of the -caine family appear in combinations with epinephrine or with another -caine member. These combinations serve useful purposes in dentistry as well as in numbing ACS Paragon Plus Environment

Page 59 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


sensitive areas during medical procedures. In 1965, citanest forte (epinephrine + prilocaine) became the first -caine/epinephrine combination to receive approval. Amide agents of the -caine family tend to have a longer duration of action compared with esters because amides generally take longer to hydrolyze99 epinephrine acts as a vasoconstrictor, helping keep the anesthetic localized in the desired area. Lidocaine has also been used in combination with a corticosteroid (dexamethasone) as well as antibiotics. Triavil (amitriptyline + perphenazine) and limbitrol DS (amitriptyline + chlordiazepoxide), originally approved in 1965 and 1977 respectively, are used to treat depression. In these combinations, amitriptyline, a tricyclic antidepressant, is used with either an antipsychotic (perphenazine) or benzodiazepine sedative (chlordiazepoxide). The remittance rate for patients treated for major depressive disorder by first-line therapies is estimated to be around 33%. As esult of this paltry remission rate, many patients continue to endure treatment-resistant depression (TRD). Various treatment strategies such as switching antidepressant and combining antidepressants amongst other strategies have been utilized. Symbyax (fluoxetine + olanzapine), approved in 2003, has been shown to be more effective in treating TRD when compared to monotherapy antidepressants.100 Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is used with olanzapine, an atypical antipsychotic. Nuedexta (DM + quinidine), approved in 2010, is prescribed for the treatment of uncontrollable emotions, such as laughing and crying. These combinations target the pseudobulbar affect (PBA), which occurs secondary in those who have either had a brain injury or neurological disorder. Patients with PBA may experience uncontrollable crying or laughing even if there is no emotional trigger. Quinidine helps increase the bioavailability of dextromethorphan through its actions as a CYP450 (CYP2D6) inhibitor. Dextromethorphan is a noncompetitive NMDA receptor antagonist.101 It is truly remarkable that two drugs, which have been used for so long, could be combined for such a unique indication. Sinemet (carbidopa + levodopa) and stalevo 100 (carbidopa + entacapone + levodopa) approved in 1975 and 2003 respectively, are used as dopamine promoters to treat Parkinson’s disease symptoms.102 Levodopa is a dopamine precursor; however, unlike dopamine, levodopa can cross the blood-brain-barrier (BBB). Once levodopa has crossed the BBB, dopamine decarboxylase converts it to dopamine. Carbidopa is a dopamine decarboxylase inhibitor which functions by inhibiting the conversion of levodopa to dopamine in the peripheral nervous system; this allows more levodopa to cross the BBB. Entacapone is a reversible, selective catechol-O-methyltransferase ACS Paragon Plus Environment


Page 60 of 135

(COMT) inhibitor that increases levodopa’s bioavailability in the brain by inhibiting its metabolism by methylation.103 Namzaric (memantine + donepezil), approved in 2014, is used to treat Alzheimer’s symptoms, although it doesn’t cure the disease.104 Memantine, originally synthesized in the 1960s as an unsuccessful antidiabetic candidate, was found to have central nervous system (CNS) properties. It wasn’t until 1989 that memantine was shown to be an (NMDA) antagonist, but with a safer therapeutic profile than other members.105 Memantine is remarkable structurally for its simplicity and symmetry; it’s adamantane core is seen only in a few other approved drugs. Its combination partner donepezil, an acetylcholinesterase inhibitor, contains an indanone heterocycle. The indanone dimethoxy groups result in 20-fold increased activity compared to an unsubstituted core. The position of the piperidine as well as bridge length between the indanone and piperidine are crucial for activity. Direct connection diminishes the potency.106 Lipophilicity is an important factor thought to facilitate blood-brain barrier penetration. The cyclopropyl moiety, as seen in buprenorphine is being seen more frequently in pharmaceuticals. This is because cyclopropyl groups can potentially increase metabolic stability and lipophilicity, while providing conformational restriction of peptide bonds, thereby slowing proteolytic cleavage.107 However, there are toxicity concerns with cyclopropylamines. For example the cyclopropylamine moiety in trovafloxacin, an antibiotic of the fluoroquinolone family, has been shown to be metabolized in vitro by first ring opening then ultimately forming a reactive electrophilic α,β-unsaturated aldehyde.108 Fluorine substituents (CF3 and F) are also seen on a few pharmaceuticals (fluoxetine and dexamethasone). Fluorine has been used as a bioisostere for hydrogen in drugs. The addition of fluorine or a fluorine containing group can have a dramatic impact on properties such as bioavailability, lipophilicity, and metabolic stability of pharmaceuticals.109 Additional factors thought to facilitate BBB penetration include size, structure, and charge. Most nervous system drugs contain basic amines (uncharged at physiological pH) and not acids (charged at physiological pH). The charged interactions can hinder BBB penetration. Molecular weight is also a major component of BBB penetration with a general cutoff for mass estimated to be around 400-600 Da, although there are exceptions.110 As compared to other disease categories such as anti-infective, nervous system pharmaceuticals tend to have smaller molecular weights overall.


Page 61 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60




Page 62 of 135

Page 63 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 24A. All Nervous System Approved Primary Combination Structures

Figure 24B. All Nervous System Approved Secondary Combination Structures

Respiratory System All 55 respiratory drug combination components are shown in Figure 25A and 25B. This combination drug category has great diversity of structures with major families highlighted in boxes. These include antihistamines, steroids, beta-lactams, -caines and -morphinans. Natural product structures range from complex (rifampin and reserpine) to simple (dextrose, epinephrine and acetyl cysteine). Five respiratory system components make it on the top 24 list. These are, pseudoephedrine, codeine, hydrocodone, phenylephrine and chlorpheniramine approved for eleven, five, three, three and three total combinations respectively. The majority of the 46 US FDA approved combinations are used as allergy and cold remedies, antibiotics to treat respiratory infections such as tuberculosis, pneumonia and bronchitis as well as bronchodilators to treat chronic obstructive pulmonary disease (COPD) and/or asthma are also seen. Two combinations are indicated for cystic fibrosis. In ACS Paragon Plus Environment


Page 64 of 135

1943, Hyocodan (homatropine + hydrocodone) became the first respiratory combination to be approved. Antitussives (codeine and DM), antihistamines (promethazine, bromodiphenhydramine, chlorpheniramine and dexbrompheniramine), NSAID (ibuprofen) and decongestant (phenylephrine) are frequently used in various combinations as cough and cold remedies. For example, tussicaps (chlorpheniramine + hydrocodone), Advil congestion relief (ibuprofen + phenylephrine) and advil allergy and congestion relief (ibuprofen + chlorpheniramine + phenylephrine) approved in 1987, 2010 and 2011 respectively, are used to treat hay fever, cold, and other allergic symptoms. In 1952, promethazine/codeine (codeine + promethazine) became the earliest cough syrup combination to be approved. This syrup is easily recognizable by its purple color. Unfortunately, the analgesic properties of codeine have frequently made it a drug of abuse. Furthermore, because both firstgeneration antihistamines and morphinans are CNS depressants, death can occur from respiratory depression if too much is taken. Mucinex DM (DM + guaifenesin) and dymista (azelastine + fluticasone) are examples of recently approved combinations (2004 and 2012 respectively) used to relieve allergy symptoms such as runny nose, watery eyes and sore throat. Muscarinic antagonists, (ipratropium bromide, umeclidinium bromide, tiotropium bromide and glycopyrronium), which aid in relaxing smooth muscles, are frequently combined with β2 adrenergic receptor agonist bronchodilators (salbutamol, salmeterol, formoterol, vilanterol and olodaterol) in the treatment of COPD and/or asthma management.111 Glucocorticoids (fluticasone, budesonide and mometasone) are used in combinations to control inflammation in COPD and asthma. Earlier muscarinic antagonists contained tropane pharmacophores. However, later members such as umeclidinium bromide and glycopyrronium bromide contain quinuclidine and pyrrolidine cores respectively. Orkambi (lumacaftor + ivacaftor) and symdeko (tezacaftor + ivacaftor), approved in 2015 and 2018 respectively, are indicated for cystic fibrosis. Cystic fibrosis, an autosomal recessive disorder, is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. CFTR, a chloride ion channel present in lung epithelium, safeguards the secretion of chloride ions and water in the airway fluid; this in turn allows mucus secretions to be cleared from the airways A deficient CFTR, which leads to decreased chloride secretion and increased sodium absorption, causes mucus secretions to become dry, thick and buildup in the airways.112 The CFTR gene, located on chromosome seven, contains approximately 180,000 base pairs. So far, more than a ACS Paragon Plus Environment

Page 65 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


thousand mutations at the CFTR have been realized.113 Both orkambi and symdeko target the Phe508del mutation, the most common CFTR mutation seen in cystic fibrosis patients.114 Ivacaftor, the first CFTR modulator approved, improves chloride transport through binding to the ion channel; this increases the likelihood that the channel is open. Lumacaftor acts as a CFTR corrector, increasing the amount of CFTR at the cell surface. However, lumacaftor + ivacaftor can cause respiratory side effects in some patients. In addition, lumacaftor, a cytochrome P-450-3A inductor, can cause undesirable protein-protein interactions with some patients. Tezacaftor, also a CFTR corrector, was developed as an alternative for patients who encounter these unwanted side effects and drug interactions with orkambi.115 Kovanaze (oxymetazoline + tetracaine), approved in 2016, is a needle-free regional anesthetic nasal spray. This distinctive indication combines a local anesthetic (tetracaine) with a decongestant (oxymetazoline). Kovanaze is indicated for regional anesthesia in dentistry on teeth A-J and 4-13 in adults. Routes of administration for respiratory combinations vary from oral (various cold remedies), inhalation (for asthma and COPD), i.v (various anti-infective penicillins), and nasal sprays (ie kovanaze).




Page 66 of 135

Page 67 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 25A. All Respiratory System Approved Primary Combination Structures

Figure 25B. All Respiratory System Approved Secondary Combination Structures

Sensory Organs All 38 sensory-organ combination structure components are presented in Figure 26A and 26B. A total of 30 US FDA combinations drugs have been approved for the treatment of various otic and ophthalmic conditions. This disease category is rich with natural products and their derivatives, which include steroids, aminoglycosides, tetracyclines, macrolides and complex macrocyclic peptide natural products like gramicidin, bacitracin, colistin and polymyxin B. Six combination components from the top 24 list have been approved for sensory organ ACS Paragon Plus Environment


Page 68 of 135

conditions. These drugs are neomycin (#2), polymyxin B (#5), hydrocortisone acetate (#10), hydrocortisone (#18), phenylephrine (#20) and prednisolone acetate (#25). In 1953, chloromycetin hydrocortisone (hydrocortisone acetate + chloramphenicol) became the first sensory organ combination to be approved for the treatment of various ear and eye infections. Ophthalmic and otic anti-infective combinations, like chloromycetin hydrocortisone, usually contain a steroid (prednisolone acetate, dexamethasone, fluorometholone acetate, hydrocortisone, loteprednol or hydrocortisone acetate) component to control inflammation in combination with an antibiotic. Polytrim (polymyxin B + trimethoprim), approved in 1988, is an ophthalmic anti-infective used to treat conjunctivitis. Pupil dilator combinations used during eye examinations are also seen. Cyclopentolate and tropicamide, both muscarinic antagonists which dilate the pupil, share structural similarities to atropine. They are used in combination with phenylephrine and 4-hydroxyamphetamine, both phenethylamine derivatives. Timolol, which is used in formulations to treat glaucoma, contains a structurally unique beta blocker. Unlike majority of beta blockers, which contain the aminopropanol attached to a phenyl substituted aromatic, timolol contains a morpholine-thiadiazole instead. Timolol treats glaucoma through the reduction of intraocular pressure by decreasing aqueous humor production.116 Timolol is used in combination with dorzolamide, a sulfonamide diuretic of the carbonic anhydrase inhibitor class and brimonidine, an α2 adrenergic agonist vasoconstrictor. Both brimonidine and dorzolamide reduce intraocular pressure functions: brimonidine by both decreasing aqueous humor synthesis as well as triggering the outflow of aqueous humor via the uveoscleral pathway117 and dorzolamide by decreasing aqueous humor production. Brimonidine is also seen in a glaucoma combination with brinzolamide, another carbonic anhydrase inhibitor. Betaxolol, another beta blocker, is used in combination with pilocarpine, a saliva production stimulator to also treat glaucoma. Betaxolol’s mechanism of action is the same as timolol. Pilocarpine lowers intraocular pressure through stimulating the outward flow of aqueous humor from the eye.118 Omidria (phenylephrine + ketorolac), approved in 2014, is the first intracameral FDA approved medication indicated for use during cataract surgery.119 Injections into the eye cavities help prevent endophthalmitis and eye infections after cataract surgery. Phenylephrine, an α1-adrenergic receptor agonist, is used with ketorolac, an NSAID. Naphazoline, a sympathomimetic vasoconstrictor and eye decongestant, is used in combinations with antazoline and pheniramine, both antihistamines, to treat allergic conjunctivitis.120 ACS Paragon Plus Environment

Page 69 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Majority of combinations in this section are given as solutions to be applied on the ear (otic route), on the eye (ophthalmic route) as well as nasally.

Figure 26A. All Sensory Organ Approved Primary Combination Structures



Figure 26B. All Sensory Organ Approved Secondary Combination Structures


Page 70 of 135

Page 71 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Oncological Drugs There continues to be an urgent need to develop oncological agents with limited side effects to effectively treat a variety of cancers. Due to the intense contemporary nature and importance of this disease category, we have chosen to divide our analysis of oncological combination drugs into three sections: classic chemotherapeutic combination agents, targeted oncological agents, and the current state as well as future opportunities in oncological drug development. The first chemotherapy agent arsphenamine was marketed for the treatment of syphilis over a century ago in the lab of Paul Ehrlich, the scientist who introduced the words ‘chemotherapy’ and ‘magic bullet.’121 Nitrogen mustards, the first cancer chemotherapy agents, were introduced in the 1940s. These were developed after examination of World War II soldiers accidentally exposed to sulfur mustards showed a reduction in bone marrow and lymph nodes. Two decades later, Skipper and colleagues, while extensively researching cures for murine leukemia, introduced the “Cell Kill” hypothesis while hypothesizing that cancer chemotherapy combinations may be superior in curing cancer.122,123 The first cancer chemotherapy combination regimen dates back to 1964, when VAMP (vincristine + amethopterin, + 6-mercapto-purine + prednisone) was used for acute lymphocytic leukemia.124 These four drugs, each used previously as monotherapy to treat acute lymphocytic leukemia in children, were given to 16 patients in a study. 14 (88%) of the patients experienced complete remission.125 Many other cancer chemotherapy combinations soon followed. However, although each one of these pharmaceuticals is FDA approved as a monotherapy, only a select few are FDA approved as combination drugs. The two latest chemotherapeutic combination agents approved are lonsurf (trifluridine + tipiracil) and vyxeos (cytarabine + daunorubicin). Lonsurf, approved in 2015, treats colorectal cancer.126 Vyxeos approved in 2017, was approved as a treatment for two acute myeloid leukemias (AML): therapy-related myeloid leukemia (t-AML) as well as AML with myelodysplasia-related changes (AML-MRC).127,128 Myelodysplasia causes a disruption in the proper formation of blood cells and some forms can ultimately lead to AML.129 As shown in Figure 27A and 27B, structural as well as mechanistic diversity is seen with platinum agents, nucleoside antimetabolites, diverse natural products (rubicin family, etoposide, bleomycin, vincristine members and taxol), and steroids. The unique mechanism of action and structures of some of these chemotherapy agents is ACS Paragon Plus Environment


Page 72 of 135

worth mentioning. Nitrogen mustards (mechlorethamine and cyclophosphamide) are metabolized in vivo to reactive aziridinium rings which can then be attacked by DNA to form covalent adducts.130 Platinum agents act as electrophilic sources for nucleophilic DNA to attack and crosslink.131 Structures containing hydrazines (dacarbazine and procarbazine) are metabolized in vivo to reactive species, such as CH3+, which alkylates DNA.132 The majority of non-FDA approved chemotherapy combinations are known by various acronyms and are used under the discretion of the physician (oncologist). The hallmark of these chemotherapeutic agents is to target and eradicate rapidly dividing cells, whether they be normal or cancerous. However, as result of this lack of selectivity, many undesirable side effects are seen with these chemotherapeutic agents. Gastrointestinal issues, myelosuppression, as well as alopecia are all common side effects seen by patients.133 Nausea and vomiting are also common side effects with chemotherapy. In 2014, akynzeo (netupitant + palonosetron), became approved for treatment of chemotherapy induced nausea and vomiting.134 Figures 27A and 27B below show various cancer chemotherapeutic agents which appear in numerous combinations. Cyclophosphoramide, doxorubicin, vincristine, etoposide and cisplatin are seen most frequently with 42, 36, 33, 32, and 25 appearances respectively. A non-exhaustive compiled list of combinations of chemotherapeutic agents can be found in the supporting info. There has been considerable effort in the pursuit of developing targeted oncological agents with less side effects. Monoclonal antibodies and synthetic small molecules are the two drug families represented as targeted agents (Figure 28). The goal of targeted oncological therapy is to design agents which block cancer growth by interfering with specific molecular pathways and molecular targets responsible for carcinogenesis.135 The year 2001 marked a groundbreaking milestone in small molecule targeted oncological agents, as Imatinib became the first approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia. Imatinib, a BCR-ABL kinase inhibitor, was immediately impactful as 76% of patients had complete cytogenetic responses.136 In 2014, a combination of dabrafenib, a BRAF inhibitor, and trametinib, a mitogen-activated protein kinase (MEK) inhibitor, was FDA approved to treat metastatic melanoma in patients who contain BRAF V600E or V600K mutations.137 In 2017, dabrafenib + trametinib indications were expanded for the treatment of non-small cell lung cancer (NSCLC) in patients with BRAF V600E mutations.138,139


Page 73 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Fifteen years prior to imatinib’s approval, orthoclone OKT3 became the first monoclonal antibody to be FDA approved to treat kidney transplant rejections.140 However, it was not until 2004, that a monoclonal antibody (bevacizumab) was approved in a combination regimen with 5-fluorouracil for treatment of metastatic carcinoma of the colon/rectum.141 In 2006, bevacizumab in combination with folfox (oxaliplatin + fluorouracil + folinic acid) was approved as a second line treatment of colon/rectal cancer.142 There continues to be active interest in the potential use of immunotherapy agents in combination with targeted oncological agents and/or chemotherapy agents. The success that immunotherapy agents such as the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor ipilimumab and the autologous dendritic cell vaccine sipuleucel-T have had in various cancer pathologies has led researchers to investigate their potential synergistic relationship if combined with targeted oncological agents. Targeted therapies have been shown to modulate biochemical pathways critical to the immune system. This can potentially be leveraged to enhance beneficial anti-tumor immune responses when combined with immunotherapy agents to overcome and kill cancerous tumors. In 2009, IFN‐α, a cytokine + bevacizumab became the first combination containing an immuno-agent to be approved for treatment of renal cancer.143 In 2015, two additional immunotherapy combinations were approved. Nivolumab, a programmed cell death protein 1 (PD1) inhibitor + ipilimumab was given accelerated approval for the treatment of melanoma. Elotuzumab, which targets signaling lymphocytic activation molecule family member 7 (SLAMF7), + lenalidomide + dexamethasone, chemotherapy agents, was FDA-approved for treatment of multiple myeloma.144 The attention in this area is likely to remain after the recent failures with immuno-oncology combinations in clinical trials. The phase III clinical trial of the PD1 inhibitor Keytruda (pembrolizumab) + indoleamine-pyrrole 2,3-dioxygenase (IDO1) inhibitor epacadostat combination failed to show that the combination showed enhanced improvement as compared to pembrolizumab in monotherapy. IDO1 is an enzyme responsible for turning the amino acid tryptophan into kynurenine in the ratelimiting step of the kynurenine pathway. The kynurenine pathway has been implicated in the regulation of immune function.145 Another clinical trial tested a combination of ipilimumab with vemurafenib, a BRAF inhibitor. Phase I trials showed hepatotoxicity in patients which led authors to conclude that clinical trials for combination drugs with two distinct mechanisms of actions should be “carefully conducted.” ACS Paragon Plus Environment

146

A variety of


Page 74 of 135

immuno-agents in combination with targeted agents and/or cancer chemotherapeutic agents are in various stages of clinical trials. Figure 28 shows a selected survey of various immuno-agents and targeted agents being seen in combinations. The two most frequently seen immuno-agents in these combinations are atezolizumab, a programmed death-ligand 1 (PD-L1) inhibitor and nivolumab. A non-comprehensive list of immuno-oncological combinations can be found in the supplementary.147 Another important point raised is the question as to why various single agents which possess trifling therapeutic activity in monotherapy are being tested in oncological combination therapies for the treatment of the same diseases. These agents are indicated only for palliative care, not the treatment of the cancer pathology.148 Recalling the basic criteria the FDA requires for combination therapies to be approved, it is worth asking if these combinations truly offer the patient a greater therapeutic benefit as opposed to one given as a monotherapy? On the other hand, cost-effective alternative strategies such as drug repurposing has also been effective in finding potential oncology agents. For example, carbonic anhydrase inhibitors (CAIs), typically used to treat glaucoma, have been extensively investigated as anti-cancer agents after research showed that cancerous cells possess high carbonic anhydrase activity.149 In one study, doxorubicin’s efficacy in treating colon cancer has been shown to increase when combined with various CAIs.150 Metformin, an antidiabetic already discussed in detail, has been shown to have involvement in an antioxidant pathway, ultimately leading to oxidative stress-induced apoptosis of breast cancer cells.151 Repurposing histone deacetylase inhibitors (HDACi) as targets in the epigenetic modulation pathway continues to be investigated. Epigenetic pathways, primarily responsible for regulating and silencing various genes, are susceptible to stress and mutations which can lead to cancer. To this end, HDACi’s such as valproic acid (which treats epilepsy) have been evaluated in various oncological combinations.152 The potential of drug repurposing as a cost-effective strategy in future oncological combinations continues to be of contemporary pursuit.


Page 75 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



Page 76 of 135

Figure 27A. Examples of Primary Cancer Chemotherapeutic Agents used in various combinations

Figure 27B. Examples of Primary and Secondary Cancer Chemotherapeutic Agents used in various combinations ACS Paragon Plus Environment

Page 77 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 28. Examples of agents being used in immuno-oncological combinations

Summary: In conclusion, this perspective represents the first comprehensive structural analysis of US FDA approved combination drugs. Since the earliest combination drug in our database was approved in 1943, combination drug outputs have been increasing throughout each decade. Hydrochlorothiazide continues to be the most frequently used small molecule component in combination drugs with indications almost exclusively for the


Page 78 of 135

cardiovascular system. Historically, drug combinations with two INNs are most prominent. However, combinations with three and four INNs are emerging more often. The nervous system disease category currently has the most drug combinations. However, anti-infective combinations continue to be on rise, particularly in helping to combat serious viruses such as HIV-1, and hepatitis C. This speaks to the difficulty in treating some of these viruses. The schemes of all eleven disease category figures are presented in a way which allows one to both appreciate new innovative drug architectures and trends while immediately recognizing the number of similar looking drugs. AUTHOR INFORMATION Corresponding Author *Phone: 520-626-0754. E-mail: [email protected] Author Contributions P.D. and M.D.D. contributed equally to the creation of this work. Notes The authors declare no competing financial interest. Biographies Munaum H. Qureshi received a B.S. in chemistry from The University of Texas at Austin in 2016. Munaum entered the graduate program in chemistry at The University of Arizona in August of 2016 and in January of 2017 joined the research group of Professor Njardarson. Michael D. Delost received a B.S. in chemistry from Gannon University in 2013. He then earned a M.S in Organic Chemistry from Youngstown State University in 2015. Mike joined the research group of Professor Njardarson in August of 2016. David T. Smith received a B.S. in chemistry from The University of North Carolina at Charlotte in December of 2012. David entered the graduate program in chemistry at The University of Arizona in August of 2013 and in January of 2014 joined the research group of Professor Njardarson. ACS Paragon Plus Environment

Page 79 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Pradipta Das received a B.Sc. (Hons.) in chemistry from Presidency College, University of Calcutta, India, in 2010. She also received her M.Sc. degree in Chemistry from Indian Institute of Technology, Guwahati, in 2012. Pradipta entered the graduate program in chemistry at The University of Arizona in August of 2012 and in January of 2013 joined the research group of Professor Njardarson. Professor Njardarson received his Ph.D. at Yale University in 2001 with Professor John L. Wood. Following postdoctoral training with Professor Samuel J. Danishefsky at The Memorial Sloan-Kettering Cancer Center he started his independent career in 2004 at Cornell University. In 2010, Professor Njardarson moved his research group to The University of Arizona. ACKNOWLEDGEMENT We would like to thank the National Science Foundation (CHE1565500) for financial support of the pharmaceutical poster outreach projects, and the resulting analysis efforts. ABBREVIATIONS AND ACRONYMS ACE, Angiotensin-Converting Enzyme; AIDS, Acquired Immune Deficiency Syndrome; ALF, Acute Liver Failure; AML, Acute Myeloid Leukemias; BBB, Blood-Brain-Barrier; BHP, Benign Prostatic Hyperplasia; CFTR, Cystic Fibrosis Transmembrane Conductance Regulator; CNS, Central Nervous System; COPD, Chronic Obstructive Pulmonary Disease; CYP450, Cytochrome P450; cytotoxic T-lymphocyte-associated protein 4, CTL4; DBO, Diazabicyclooctanes; DHP, Dihydropyridine; DHT, Dihydrotestosterone; DM, Dextromethorphan; DPP,

Dipeptidyl-Peptidase;

HCT,

Hydrochlorothiazide

(when

in

a

combination

drug);

HCTZ,

Hydrochlorothiazide; HIV-1, Human Immunodeficiency Virus-1; INN, International Nonproprietary Names; MET, Metformin; MRC, Myelodysplasia-Related Changes; NAD, Nicotinamide Adenine Dinucleotide; NADP, Nicotinamide Adenine Dinucleotide Phosphate; NAPQI, N-Acetyl-p-benzoquinone Imine; NMDA, N-MethylD-Aspartate; NS 3A/4A/5A/5B= Nonstructural Protein 3A/4A/5A/5B; NSAID, Non-Steroidal AntiInflammatory Drugs; NSCLC, Non-Small Cell Lung Cancer; PBA, Pseudobulbar Affect; SAD, Seasonal Allergic



Page 80 of 135

Rhinitis; SERM, Selective Estrogen Receptor modulator; SSRI, Selective Serotonin Reuptake Inhibitor; XR, Extended Release. SUPPORTING INFORMATION The Supporting Information is available free of charge on the ACS Publications website at DOI: Combination drugs database tables (PDF) List of all molecules with SMILES strings (XLSX) REFERENCES

(1) a) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. A graphical journey of innovative organic architectures that have improved our lives J. Chem. Ed. 2010, 87, 1348-1349, b) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. An in-pharm-ative educational poster anthology highlighting the therapeutic agents that chronicle our medicinal history. J. Chem. Ed. 2013, 90, 1403-1405, c) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. Data-mining for sulfur and fluorine: an evaluation of pharmaceuticals to reveal opportunities for drug design and discovery. J. Med. Chem. 2014, 57, 2832-2842, d) Smith, B. R.; Eastman, C. M.; Njardarson, J. T. Beyond C, H, O, and N! analysis of the elemental composition of U.S. FDA approved drug architectures. J. Med. Chem. 2014, 57, 9764-9773, e) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 2014, 57, 10257-10274, f) Scott, K. A.; Njardarson, J. T. Analysis of US FDA drugs containing sulfur atoms. Topics in Current Chemistry – Sulfur Chemistry 2018, 376, 1-34 and g) Delost, M. D.; Smith, D. T.; Anderson, B. J.; Njardarson, J. T. From oxiranes to oligomers: architectures of US FDA approved pharmaceuticals containing oxygen heterocycles J. Med. Chem. 2018, 61, ASAP. DOI: 10.1021/acs.jmedchem.8b00876. (2) There are 25 approved combinations for which we were unable to find an approval year. (3) Finland, M. Combinations of antimicrobial drugs: trimethoprim-sulfamethoxazole. New Engl. J. Med. 1974, 12, 624-627. ACS Paragon Plus Environment

Page 81 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(4) Richardson, P. Fluorination methods for drug discovery and development. Expert Opin. Drug Discov. 2016, 11, 983-999. (5) Messerli, F. H.; Bangalore, S. Half a century of hydrochlorothiazide: facts, fads, fiction, and follies. Am. J. Med. 2011, 124, 896-899. (6) Bryan, J. From snake venom to ACE inhibitor - The discovery and rise of captopril. Pharm. J. 2009, 282, 455456. (7) Wood, J. M.; Maibaum, J. In Aspartic Acid Proteases as Therapeutic Targets, Wiley-VCH Verlag GmbH & Co. KGaA: 2011, Chapter 10, 265-296. (8) Moser, M. Rationale for combination therapy in the management of hypertension. J Clin Hypertens. 2003, 5, (6 Suppl.4):17–25. (9) Borghi, C.; Cicero, A. F. G. Fixed combination of zofenopril plus hydrochlorothiazide in the management of hypertension: a review of available data. Vasc. Health Risk. Manag. 2006, 2, 341-349. (10) Eccles, R. Substitution of phenylephrine for pseudoephedrine as a nasal decongeststant. An illogical way to control methamphetamine abuse. Brit. J. Clin. Pharmaco. 2007, 63, 10-14. (11) Sussman, G. L.; Mason, J.; Compton, D.; Stewart, J.; Ricard, N. The efficacy and safety of fexofenadine HCl and pseudoephedrine, alone and in combination, in seasonal allergic rhinitis. J. Allergy Clin. Immunol. 1999, 104, 100-106. (12) Church, M. K.; Church, D. S. Pharmacology of antihistamines. Indian J. Dermatol. 2013, 58, 219-224. (13) Simon, F. E. R.; Simons, K. J. H(1) Antihistamines: current status and future directions. World Allergy Organ. J. 2008, 1, 145-155. (14) Brune, K.; Renner, B.; Tiegs, G. Acetaminophen/paracetamol: a history of errors, failures and false decisions. Eur. J. Pain. 2015, 19, 953-965. (15) Renner, B.; Clarke, G.; Grattan, T.; Beisel, A.; Mueller, C.; Werner, U.; Kobal, G.; Brune, K. Caffeine accelerates absorption and enhances the analgesic effect of acetaminophen. J. Clin. Pharmacol. 2007, 47, 715726.


Page 82 of 135

(16) Goldstein, J.; Silberstein, S. D.; Saper, J. R.; Ryan, R. E., Jr.; Lipton, R. B. Acetaminophen, aspirin, and caffeine in combination versus ibuprofen for acute migraine: results from a multicenter, double-blind, randomized, parallel-group, single-dose, placebo-controlled study. Headache. 2006, 46, 444-453. (17) Sawaddiruk, P. Tramadol hydrochloride/acetaminophen combination for the relief of acute pain. Drugs Today. 2011, 47, 763-772. (18) Albano, E.; Rundgren, M.; Harvison, P. J.; Nelson, S. D.; Moldeus, P. Mechanisms of N-acetyl-pbenzoquinone imine cytotoxicity. Mol. Pharmacol. 1985, 28, 306-311. (19) Rapoport, A.; Stang, P.; Gutterman, D. L.; Cady, R.; Markley, H.; Weeks, R.; Saiers, J.; Fox, A. W. Analgesic rebound headache in clinical practice: data from a physician survey. Headache. 1996, 36, 14-19. (20) Meek, I. L.; van de Laar, M. A. F. J.; Vonkeman, H. E. Non-steroidal anti-Inflammatory drugs: an overview of cardiovascular risks. Pharmaceuticals. 2010, 3, 2146-2162. (21) Sneader, W. The discovery of aspirin: a reappraisal. BMJ Brit. Med. J. 2000, 321, 1591-1594. (22) Undas, A.; Brummel-Ziedins, K. E.; Mann, K. G. Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood. 2007, 109, 2285-2292. (23) Veltri, K. T. Yosprala: a fixed dose combination of aspirin and omeprazole. Cardiol. Rev. 2018, 26, 50-53. (24) Strack, T. Metformin: a review. Drugs Today. 2008, 44, 303-314. (25) Bailey, C. J. Metformin: historical overview. Diabetologia. 2017, 60, 1566-1576. (26) Home, P.D. Impact of the UKPDS—an overview. Diabet. Med. 2008, 25, 2-8. (27) Chaudhury, A.; Duvoor, C.; Reddy Dendi, V. S.; Kraleti, S.; Chada, A.; Ravilla, R.; Marco, A.; Shekhawat, N. S.; Montales, M. T.; Kuriakose, K.; Sasapu, A.; Beebe, A.; Patil, N.; Musham, C. K.; Lohani, G. P.; Mirza, W. Clinical review of antidiabetic drugs: implications for type 2 diabetes mellitus management Frontiers Endocrinol. 2017, 8, 1-12. (28) Lavernia, F.; Adkins, S. E.; Shubrook, J. H. Use of oral combination therapy for type 2 diabetes in primary care: Meeting individualized patient goals. Postgrad. Med. 2015, 127, 808-817. (29) Fonseca, V. Effect of thiazolidinediones on body weight in patients with diabetes mellitus. Am. J. Med. ACS Paragon Plus Environment

Page 83 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2003, 115 Suppl 8A, 42s-48s. (30) Mannucci, E.; Tesi, F.; Bardini, G.; Ognibene, A.; Petracca, M. G.; Ciani, S.; Pezzatini, A.; Brogi, M.; Dicembrini, I.; Cremasco, F.; Messeri, G.; Rotella, C. M. Effects of metformin on glucagon-like peptide-1 levels in obese patients with and without Type 2 diabetes. Diabetes Nutr. Metab. 2004, 17, 336-342. (31) Moon, M. K.; Hur, K. Y.; Ko, S. H.; Park, S. O.; Lee, B. W.; Kim, J. H.; Rhee, S. Y.; Kim, H. J.; Choi, K. M.; Kim, N. H. Committee of clinical practice guidelines of the korean diabetes, A., combination therapy of oral hypoglycemic agents in patients with type 2 diabetes mellitus. Diabetes Metab. J. 2017, 41, 357-366. (32) Pletzer, B.A.; Kerschbaum, H.H. 50 years of hormonal contraception—time to find out, what it does to our brain. Front Neurosci. 2014, 8, 1-6. (33) Keam, S. J.; Wagstaff, A. J. Ethinylestradiol/drospirenone: a review of its use as an oral contraceptive. Treat. Endocrinol. 2003, 2, 49-70. (34) Lemke, T. L.; Williams, D. A.; Roche, V. F.; Zito, S. W. In Foye's Principles of Medicinal Chemistry, 7th ed.; Lippincott Williams & Wilkins: Baltimore, 2013; pp 1393. (35) Perry, C. M.; Faulds, D. Lamivudine. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV infection. Drugs. 1997, 53, 657-680. (36) Larson, K. B.; Wang, K.; Delille, C.; Otofokun, I.; Acosta, E. P. Pharmacokinetic enhancers in HIV therapeutics. Clin. Pharmacokinet. 2014, 53, 865-872. (37) Eron, J. J.; Benoit, S. L.; Jemsek, J.; MacArthur, R. D.; Santana, J.; Quinn, J. B.; Kuritzkes, D. R.; Fallon, M. A.; Rubin, M. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. N. Engl. J. Med. 1995, 333, 1662-1669. (38) Fabbiani, M.; Gagliardini, R.; Ciccarelli, N.; Quiros Roldan, E.; Latini, A.; d’Ettorre, G.; Antinori, A.; Castagna, A.; Orofino, G.; Francisci, D.; Chinello, P.; Madeddu, G.; Grima, P.; Rusconi, S.; Del Pin, B.; Lombardi, F.; D’Avino, A.; Focà, E.; Colafigli, M.; Cauda, R.; Di Giambenedetto, S.; De Luca, A.; Group, A.M. S.. Atazanavir/ritonavir with lamivudine as maintenance therapy in virologically suppressed HIV-infected


Page 84 of 135

patients: 96-week outcomes of a randomized trial J. Antimicrob. Chemother. 2018, 73, 1955-1964. (39) Frampton, J. E.; Perry, C. M. Emtricitabine: a review of its use in the management of HIV infection. Drugs 2005, 65, 1427-1448. (40) Masho, S. W.; Wang, C.-L.; Nixon, D. E. Review of tenofovir-emtricitabine. Ther. Clin. Risk Manag. 2007, 3, 1097-1104. (41) Wong, E.; Trustman, N.; Yalong, A. HIV pharmacotherapy: A review of integrase inhibitors. JAAPA. 2016, 29, 36-40. (42) Tsiang, M.; Jones, G. S.; Goldsmith, J.; Mulato, A.; Hansen, D.; Kan, E.; Tsai, L.; Bam, R. A.; Stepan, G.; Stray, K. M.; Niedziela-Majka, A.; Yant, S. R.; Yu, H.; Kukolj, G.; Cihlar, T.; Lazerwith, S. E.; White, K. L.; Jin, H. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob. Agents Ch. 2016, 60, 7086-7097. (43) Deeks, E. D. Cobicistat: a review of its use as a pharmacokinetic enhancer of atazanavir and darunavir in patients with HIV-1 infection. Drugs. 2014, 74, 195-206. (44) Fares, H.; DiNicolantonio, J. J.; O'Keefe, J. H.; Lavie, C. J. Amlodipine in hypertension: a first-line agent with efficacy for improving blood pressure and patient outcomes. Open Heart. 2016, 3, e000473, 1-7. (45) Ishizuka, T.; Fujimori, I.; Kato, M.; Noji-Sakikawa, C.; Saito, M.; Yoshigae, Y.; Kubota, K.; Kurihara, A.; Izumi, T.; Ikeda, T.; Okazaki, O. Human carboxymethylenebutenolidase as a bioactivating hydrolase of olmesartan medoxomil in liver and intestine. J. Biol. Chem. 2010, 285, 11892-11902. (46) Zisaki, A.; Miskovic, L.; Hatzimanikatis, V. Antihypertensive drugs metabolism: an update to pharmacokinetic profiles and computational approaches. Curr. Pharm. Des. 2015, 21, 806-822. (47) Waksman, S. A.; Lechevalier, H. A. Neomycin, a new antibiotic active against streptomycin-resistant bacteria, including tuberculosis organisms. Science. 1949, 109, 305-307. (48) Macdonald, R. H.; Beck, M., Neomycin: a review with particular reference to dermatological usage. Clin. Exp. Dermatol. 1983, 8, 249-258.


Page 85 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(49) Gupta, S.; Govil, D.; Kakar, P. N.; Prakash, O.; Arora, D.; Das, S.; Govil, P.; Malhotra, A. Colistin and polymyxin B: a re-emergence. Indian J. Crit. Care Med. 2009, 13, 49-53. (50) Johnson, B. A.; Anker, H.; Meleney, F. L. Bacitracin: a new antibiotic produced by a member of the B. Subtilis group. Science. 1945, 102, 376-377. (51) Greenhouse, J. M.; Ryle, W. C. Combined bacitracin-neomycin ointment in treatment of pyogenic infections of the skin. AMA Arch. Derm. Syphilol. 1954, 69, 366-367. (52) Dubos, R. J. Studies on a bactericidal agent extracted from a soil bacillus : I. preparation of the agent. its activity in vitro. J. Exp. Med. 1939, 70, 1-10. (53) Dubos, R. J. Studies on a bactericidal agent extracted from a soil bacillus : ii. Protective effect of the bactericidal agent against experimental pneumococcus infections in mice. J. Exp. Med. 1939, 70, 11-17. (54) Lim, L. M.; Ly, N.; Anderson, D.; Yang, J. C.; Macander, L.; Jarkowski, A.; Forrest, A.; Bulitta, J. B.; Tsuji, B. T. Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacotherapy. 2010, 30, 1279-1291. (55) Podolsky , S. H.; Greene , J. A. Combination drugs — hype, harm, and hope. New Engl. J. Med. 2011, 365, 488-491. (56) Clissold, S. P.; Todd, P. A.; Campoli-Richards, D. M. Imipenem/cilastatin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1987, 33, 183-241. (57) Timmins, G. S.; Deretic, V. Mechanisms of action of isoniazid. Mol. Micribiol. 2006, 62, 1220-1227. (58) Lomovskaya, O.; Sun, D.; Rubio-Aparicio, D.; Nelson, K.; Tsivkovski, R.; Griffith, D. C.; Dudley, M. N. Vaborbactam: spectrum of beta-lactamase inhibition and impact of resistance mechanisms on activity in enterobacteriaceae. Antimicrob.Agents Ch. 2017, 61, e01443-17. (59) Zhanel, G. G.; Lawson, C. D.; Adam, H.; Schweizer, F.; Zelenitsky, S.; Lagace-Wiens, P. R.; Denisuik, A.; Rubinstein, E.; Gin, A. S.; Hoban, D. J.; Lynch, J. P., 3rd; Karlowsky, J. A. Ceftazidime-avibactam: a novel cephalosporin/beta-lactamase inhibitor combination Drugs. 2013, 73, 159-77. (60) Coleman, K. Diazabicyclooctanes (DBOs): a potent new class of non-β-lactam β-lactamase inhibitors.


Page 86 of 135

Curr. Opin. Microbiol. 2011, 14, 550-555. (61) Lahiri, S. D.; Johnstone, M. R.; Ross, P. L.; McLaughlin, R. E.; Olivier, N. B.; Alm, R. A. Avibactam and class c β-Lactamases: mechanism of inhibition, conservation of the binding Pocket, and implications for resistance. Antimicrob. Agents Chemother. 2014, 58, 5704-5713. (62) Hunter, P. Not boring at all. Boron is the new carbon in the quest for novel drug candidates. EMBO Rep. 2009, 10, 125-128. (63) Hecker, S. J.; Reddy, K. R.; Totrov, M.; Hirst, G. C.; Lomovskaya, O.; Griffith, D. C.; King, P.; Tsivkovski, R.; Sun, D.; Sabet, M.; Tarazi, Z.; Clifton, M. C.; Atkins, K.; Raymond, A.; Potts, K. T.; Abendroth, J.; Boyer, S. H.; Loutit, J. S.; Morgan, E. E.; Durso, S.; Dudley, M. N. Discovery of a cyclic boronic acid β-lactamase inhibitor (RPX7009) with utility vs class A serine carbapenemases. J. Med. Chem. 2015, 58, 3682-3692. (64) Allington, D. R.; Rivey, M. P. Quinupristin/dalfopristin: A therapeutic review. Clin. Ther. 2001, 23, 24-44. (65) Prachayasittikul, V.; Prachayasittikul, S.; Ruchirawat, S.; Prachayasittikul. V. 8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications. Drug Des. Dev. Ther. 2013, 7, 1157-1178. (66) Mehra, A.; Sarkar, S.; Basu, D. Lomotil (Diphenoxylate) dependence in India. Indian J. Psychol. Med. 2013, 35, 248-250. (67) Enns, G. M.; Berry , S. A.; Berry , G. T.; Rhead , W. J.; Brusilow , S. W.; Hamosh , A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. New Engl. J. Med. 2007, 356, 2282-2292. (68) Ornellas, T.; Chavez, B. Naltrexone SR/Bupropion SR (Contrave): A new approach to weight loss in obese adults Pharm. Ther. 2011, 36, 255-262. (69) Rosenstock, J.; Inzucchi, S. E.; Seufert, J.; Fleck, P. R.; Wilson, C. A.; Mekki, Q. Initial combination therapy with alogliptin and pioglitazone in drug-naïve patients with type 2 diabetes. Diabetes Care 2010, 33, 2406-2408. (70) Neff, K. M.; Nawarskas, J. J. Hydrochlorothiazide versus chlorthalidone in the management of hypertension. Cardiol. Rev. 2010, 18, 51-56.


Page 87 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(71) Carter, B. L.; Ernst, M. E.; Cohen, J. D. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension. 2004, 43, 4-9. (72) Vongpatanasin, W. Hydrochlorothiazide (HCTZ) is not the most useful nor versatile thiazide diuretic Curr. Opin. Cardiol. 2015, 30, 361-365. (73) Mitka, M. Experts argue not all diuretics the same. JAMA. 2007, 298, 31-31. (74) Vidt, D. G. Mechanism of action, pharmacokinetics, adverse effects, and therapeutic uses of amiloride hydrochloride, a new potassium-sparing diuretic. Pharmacotherapy 1981, 1, 179-187s (75) Malik, M. A.; Wani, M. Y.; Al-Thabaiti, S. A.; Shiekh, R. A. Tetrazoles as carboxylic acid isosteres: chemistry and biology. J. Incl. Phenom. Macrocycl Chem. 2014, 78, 15-37. (76) Fleckenstein, A. History of calcium antagonists. Circ. Res. 1983, 52, I3-16. (77) Packer, M.; Frishman, W. H. Verapamil therapy for stable and unstable angina pectoris: Calcium channel antagonists in perspective. Am. J. Cardiol. 1982, 50, 881-885. (78) Humbert, X.; Roule, V.; Milliez, P.; Alexandre, J. Verapamil and vasospastic angina: underuse in the elderly population. J. Geriatr. Cardiol. 2017, 14, 430-435. (79) Osswald, H.; Schnermann, J. Methylxanthines and the kidney. In Methylxanthines, Springer Berlin Heidelberg: Berlin, Heidelberg, 2011, 391-412. (80) Eichenfield, L. F.; Tom, W. L.; Berger, T. G.; Krol, A.; Paller, A. S.; Schwarzenberger, K.; Bergman, J. N.; Chamlin, S. L.; Cohen, D. E.; Cooper, K. D.; Cordoro, K. M.; Davis, D. M.; Feldman, S. R.; Hanifin, J. M.; Margolis, D. J.; Silverman, R. A.; Simpson, E. L.; Williams, H. C.; Elmets, C. A.; Block, J.; Harrod, C. G.; Begolka, W. S.; Sidbury, R. Guidelines of care for the management of atopic dermatitis: Section 2. Management and treatment of atopic dermatitis with topical therapies. J. Am. Acad. Dermatol. 2014, 71, 116-132. (81) Humbert, P.; Treffel, P.; Chapuis, J.-F.; Buchet, S.; Derancourt, C.; Agache, P. The tetracyclines in dermatology. J. Am. Acad. Dermatol. 1991, 25, 691-697.


Page 88 of 135

(82) Crowley, P. D.; Gallagher, H. C. Clotrimazole as a pharmaceutical: past, present and future. J. Appl. Microbiol. 2014, 117, 611-617. (83) Del Rosso, J. Q. What is the role of benzoyl peroxide cleansers in acne management?: Do they decrease propionibacterium acnes counts? Do they reduce acne lesions? J. Clin. Aesthet. Dermatol. 2008, 1, 48-51. (84) Torok, H. M. A comprehensive review of the long-term and short-term treatment of melasma with a triple combination cream. Am. J. Clin. Dermatol. 2006, 7, 223-230. (85) Menter, A.; Korman, N. J.; Elmets, C. A.; Feldman, S. R.; Gelfand, J. M.; Gordon, K. B.; Gottlieb, A.; Koo, J. Y. M.; Lebwohl, M.; Lim, H. W.; Van Voorhees, A. S.; Beutner, K. R.; Bhushan, R. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J. Am. Acad. Dermatol. 2009, 60, 643-659. (86) Wu, C.; Kapoor, A. Dutasteride for the treatment of benign prostatic hyperplasia. Expert Opin. Pharmaco. 2013, 14, 1399-1408. (87) Lowe, F. C. Summary of clinical experiences with tamsulosin for the treatment of benign prostatic hyperplasia. Rev. Urol. 2005, 7, S13-S21. (88) Williams-Frame, A.; Carpenter, J. S. Costs of hormonal and nonhormonal prescription medications for hot flashes. Women's Health. 2009, 5, 497-502. (89) Hale, R.W.; Niebyl, J. Bendectin: how a safe and effective drug was removed from the market by our legal system. ACOG Clin. Rev. 2012, 17, 25-27. (90) Ornstein, M.; Einarson, A.; Koren G. Bendectin/Diclectin for morning sickness: A canadian follow-up of an american tragedy. Reprod Toxicol. 1995, 9, 1-6. (91) Nuangchamnong, N.; Niebyl, J. Doxylamine succinate–pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview. Int. J. Women's Health. 2014, 6, 401-409. (92) Lesinurad/allopurinol (Duzallo) for gout-associated hyperuricemia. Med. Lett. Drugs Ther. 2017. 59, 182183.


Page 89 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(93) Komm, B. S.; Chines, A. A. Bazedoxifene: the evolving role of third-generation selective estrogen-receptor modulators in the management of postmenopausal osteoporosis. Ther. Adv. Muskuloskelet. Dis. 2012, 4, 21-34. (94) Buckley, N.; Eddleston, M.; Szinicz, L. Oximes for acute organophosphate pesticide poisoning. Cochrane Database Syst Rev. 2005, 1. (95) Tfelt-Hansen, P.; Saxena, P. R.; Dahlöf, C.; Pascual, J.; Láinez, M.; Henry, P.; Diener, H. C.; Schoenen, J.; Ferrari, M. D.; Goadsby, P. J. Ergotamine in the acute treatment of migraine: a review and European consensus. Brain. 2000, 123, 9-18. (96) Antonaci, F.; Ghiotto, N.; Wu, S.; Pucci, E.; Costa, A. Recent advances in migraine therapy. SpringerPlus 2016, 5, 637. (97) Ferrari, M. D.; Saxena, P. R. Clinical effects and mechanism of action of sumatriptan in migraine. Clin. Neurol. Neurosurg. 1992, 94, Suppl, S73-77. (98) Wilkinson, M.; Pfaffenrath, V.; Schoenen, J.; Diener, H. C.; Steiner, T. J. Migraine and cluster headache-their management with sumatriptan: a critical review of the current clinical experience. Cephalalgia. 1995, 15, 337-357. (99) Lagan, G.; McLure, H. A. Review of local anaesthetic agents. Curr. Anaesth. Crit. Care. 2004, 15, 247-254. (100) Brunner, E.; Tohen, M.; Osuntokun, O.; Landry, J.; Thase, M. E. Efficacy and safety of olanzapine/fluoxetine combination vs fluoxetine monotherapy following successful combination therapy of treatment-resistant major depressive disorder. Neuropsychopharmacol. 2014, 39, 2549-2559. (101) Cruz, M. P. Nuedexta for the treatment of pseudobulbar affect: a condition of involuntary crying or laughing. Pharm. Ther. 2013, 38, 325-328. (102) Brooks, D. J. Optimizing levodopa therapy for Parkinson’s disease with levodopa/carbidopa/entacapone: implications from a clinical and patient perspective. Neuropsych. Dis. Treat. 2008, 4, 39-47. (103) Seeberger, L. C.; Hauser, R. A. Levodopa/carbidopa/entacapone in Parkinson's disease. Expert Rev. Neurother. 2009, 9, 929-940. (104) Greig, S. L. Memantine ER/Donepezil: a review in alzheimer's disease. CNS Drugs. 2015, 29, 963-970.


Page 90 of 135

(105) Witt, A.; Macdonald, N.; Kirkpatrick, P. Memantine hydrochloride. Nature Rev. Drug Discov. 2004, 3, 109-110. (106) Sugimoto, H.; Iimura, Y.; Yamanishi, Y.; Yamatsu, K. Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride and related compounds. J. Med. Chem. 1995, 38, 4821-4829. (107) Talele, T. T., The “cyclopropyl fragment” is a versatile player that frequently appears in preclinical/clinical drug molecules. J. Med. Chem. 2016, 59, 8712-8756. (108) Sun, Q.; Zhu, R.; Foss, F. W.; Macdonald, T. L. In vitro Metabolism of a model cyclopropylamine to reactive intermediate: insights into trovafloxacin-induced hepatotoxicity. Chem. Res. Toxicol. 2008, 21, 711-719. (109) Liang, T.; Neumann, C. N.; Ritter, T. Introduction of fluorine and fluorine-containing functional groups. Angew. Chem. Int. Ed. 2013, 52, 8214-8264. (110) Banks, W. A. Characteristics of compounds that cross the blood-brain barrier. BMC Neurol. 2009, 9 (Suppl 1), S3-S3. (111) Alagha, K.; Palot, A.; Sofalvi, T.; Pahus, L.; Gouitaa, M.; Tummino, C.; Martinez, S.; Charpin, D.; Bourdin, A.; Chanez, P. Long-acting muscarinic receptor antagonists for the treatment of chronic airway diseases. Ther. Adv. Chron. Dis. 2014, 5, 85-98. (112) Vankeerberghen, A.; Cuppens, H.; Cassiman, J. J. The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions. J. Cyst. Fibros. 2002, 1, 13-29. (113) Rowe, S. M.; Miller, S.; Sorscher, E. J. Cystic Fibrosis. New Engl. J. Med. 2005, 352, 1992-2001. (114) Wainwright, C. E.; Elborn, J. S.; Ramsey, B. W.; Marigowda, G.; Huang, X.; Cipolli, M.; Colombo, C.; Davies, J. C.; De Boeck, K.; Flume, P. A.; Konstan, M. W.; McColley, S. A.; McCoy, K.; McKone, E. F.; Munck, A.; Ratjen, F.; Rowe, S. M.; Waltz, D.; Boyle, M. P. Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. New Engl. J. Med. 2015, 373, 220-231. (115) Taylor-Cousar, J. L.; Munck, A.; McKone, E. F.; van der Ent, C. K.; Moeller, A.; Simard, C.; Wang, L. ACS Paragon Plus Environment

Page 91 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


T.; Ingenito, E. P.; McKee, C.; Lu, Y.; Lekstrom-Himes, J.; Elborn, J. S. Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. New Engl. J. Med. 2017, 377, 2013-2023. (116) Ichhpujani, P.; Katz, L. J. Efficacy, safety and tolerability of combination therapy with timolol and dorzolamide in glaucoma and ocular hypertension. Drug. Healthc. Patient. Saf. 2010, 2, 73-83. (117) Cantor, L. B. Brimonidine in the treatment of glaucoma and ocular hypertension. Ther. Clin. Risk Manag. 2006, 2, 337-346. (118) Tătaru, C. P.; Purcărea, V. L. Antiglaucoma pharmacotherapy. J. Med. Life 2012, 5, 247-251. (119) Lawuyi, L. E.; Gurbaxani, A. The clinical utility of new combination phenylephrine/ketorolac injection in cataract surgery. Clin. Ophthalmol. 2015, 9, 1249-1254. (120) Greiner, J. V.; Udell, I. J. A comparison of the clinical efficacy of pheniramine maleate/naphazoline hydrochloride ophthalmic solution and olopatadine hydrochloride ophthalmic solution in the conjunctival allergen challenge model. Clin. Ther. 2005, 27, 568-577. (121) Williams, K. J. The introduction of ‘chemotherapy’ using arsphenamine – the first magic bullet. J. Royal Soc. Med. 2009, 102, 343-348. (122) Skipper, H. E.; Schabel, F. R. Jr.; Wilcox, W. S. Experimental evaluation of potential anticancer agents. XII. On the criteria and kinetics associated with “curability” of experimental leukemia. Cancer Chemother. Rep. 1964, 35, 1–111. (123) Lichtman, M. A.; Spivak, J. L.; Boxer, L. A.; Shattil, S. J.; Henderson, E. S. Commentary on and reprint of Freireich EJ, Karon M, Frei E III, Quadruple combination therapy (VAMP) for acute lymphocytic leukemia of childhood, in Proceedings of the American Association for Cancer Research (1964) 5:20. In Hematology: Landmark Papers of the Twentieth Century, Academic Press: San Diego, 2000, 655-657. (124) DeVita, V. T.; Chu, E. A history of cancer chemotherapy. Cancer Res. 2008, 68, 8643-8653. (125) Freireich, E. J.; Karon, M.; Frei, E. III. Quadruple combination therapy (VAMP) for acute lymphocytic leukemia of childhood. Proc. Am. Assoc. Cancer Res. 1964, 5, 20. (126) Kish, T.; Uppal, P. Trifluridine/Tipiracil (Lonsurf) for the treatment of metastatic colorectal cancer.


Page 92 of 135

P.T. 2016, 41, 314-325. (127) Lin, T. L.; Newell, L. F.; Stuart, R. K.; Michaelis, L. C.; Rubenstein, S. E.; Pentikis, H. S.; Callahan, T.; Alvarez, D.; Mayer, L. D.; Louie, A. C. CPX-351 ((Cytarabine:Daunorubicin) liposome injection, (Vyxeos)) does not prolong Qtcf intervals, requires no dose adjustment for impaired renal function and induces high rates of complete remission in acute myeloid leukemia. Blood. 2015, 126, 2510-2510. (128) Lancet, J.; Uy, G.; Cortes, J.; Newell.; Lin, T; Ritchie, E.; Stuart, R.; Strickland, A.; Hogge, D.; Solomon, S.; Stone, R.; Bixby, D.; Kolitz, J.; Schiller, G.; Wieduwilt, J.; Ryan, D.; Hoering, A.; Chiarella, M.; Louie, A.; Medeiros, B. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J. Clin. Oncol. 2016, 34:15 suppl. 7000. (129) Adès, L.; Itzykson, R.; Fenaux, P. Myelodysplastic syndromes. The Lancet. 2014, 383, 2239-2252. (130) Masta, A.; Gray, P. J.; Phillips, D. R., Nitrogen mustard inhibits transcription and translation in a cell free system. Nucleic Acids Res. 1995, 23, 3508-3515. (131) Dasari, S.; Tchounwou, P. B., Cisplatin in cancer therapy: molecular mechanisms of action. Eur. J. Pharmacol 2014, 0, 364-378. (132) Armand, J. P.; Ribrag, V.; Harrousseau, J. L.; Abrey, L. Reappraisal of the use of procarbazine in the treatment of lymphomas and brain tumors. Ther. Clin. Risk. Manag. 2007, 3, 213-224. (133) Gerber, D. E. Targeted therapies: a new generation of cancer treatments. Am. Fam. Physician 2008, 77, 311-319. (134) Raedler, L. A. Akynzeo (Netupitant and Palonosetron), a dual-acting oral agent, approved by the FDA for the prevention of chemotherapy-induced nausea and vomiting. Am. Health Drug Benefits 2015, 8, 44-48. (135) Joo, W. D.; Visintin, I.; Mor, G. Targeted cancer therapy – Are the days of systemic chemotherapy numbered? Maturitas 2013, 76, 308-314. (136) O'Brien, S. G.; Guilhot, F.; Larson, R. A.; Gathmann, I.; Baccarani, M.; Cervantes, F.; Cornelissen, J. J.; Fischer, T.; Hochhaus, A.; Hughes, T.; Lechner, K.; Nielsen, J. L.; Rousselot, P.; Reiffers, J.; Saglio, G.; Shepherd, J.; Simonsson, B.; Gratwohl, A.; Goldman, J. M.; Kantarjian, H.; Taylor, K.; Verhoef, G.; Bolton, A. ACS Paragon Plus Environment

Page 93 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


E.; Capdeville, R.; Druker, B. J. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 2003, 348, 994-1004. (137) Menzies, A. M.; Long, G. V. Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. Clin. Cancer Res. 2014, 20, 2035-2043. (138) Long, G. V.; Stroyakovskiy, D.; Gogas, H.; Levchenko, E.; de Braud, F.; Larkin, J.; Garbe, C.; Jouary, T.; Hauschild, A.; Grob, J. J.; Chiarion-Sileni, V.; Lebbe, C.; Mandala, M.; Millward, M.; Arance, A.; Bondarenko, I.; Haanen, J. B.; Hansson, J.; Utikal, J.; Ferraresi, V.; Kovalenko, N.; Mohr, P.; Probachai, V.; Schadendorf, D.; Nathan, P.; Robert, C.; Ribas, A.; DeMarini, D. J.; Irani, J. G.; Swann, S.; Legos, J. J.; Jin, F.; Mookerjee, B.; Flaherty, K. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet, 2015, 386, 444-451. (139) Robert, C.; Karaszewska, B.; Schachter, J.; Rutkowski, P.; Mackiewicz, A.; Stroiakovski, D.; Lichinitser, M.; Dummer, R.; Grange, F.; Mortier, L.; Chiarion-Sileni, V.; Drucis, K.; Krajsova, I.; Hauschild, A.; Lorigan, P.; Wolter, P.; Long, G. V.; Flaherty, K.; Nathan, P.; Ribas, A.; Martin, A. M.; Sun, P.; Crist, W.; Legos, J.; Rubin, S. D.; Little, S. M.; Schadendorf, D. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 2015, 372, 30-39. (140) Liu, J. K. H. The history of monoclonal antibody development – progress, remaining challenges and future innovations. Ann. Med. Surg. 2014, 3, 113-116. 141) Gruenberger, B.; Starlinger, P.; Messinger, E.; Oehlberger, L.; Weibrecht, S.; Jonas, J. P.; Weitmayr, B.; Gruenberger, T., 5-FU based chemotherapy with bevacizumab in synchronous metastatic colorectal cancer patients with bleeding primary tumor. J. Clin. Oncol. 2016, 34 (15_suppl), e23208-e23208. (142) Cohen, M. H.; Gootenberg, J.; Keegan, P.; Pazdur, R. FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer. Oncologist 2007, 12, 356-361. 143) Summers, J.; Cohen, M. H.; Keegan, P.; Pazdur, R. FDA drug approval summary: bevacizumab plus interferon for advanced renal cell carcinoma. Oncologist 2010, 15, 104-111. (144) Gormley, N. J.; Ko, C. W.; Deisseroth, A.; Nie, L.; Kaminskas, E.; Kormanik, N.; Goldberg, K. B.;


Page 94 of 135

Farrell, A. T.; Pazdur, R. FDA drug approval: elotuzumab in combination with lenalidomide and dexamethasone for the treatment of relapsed or refractory multiple myeloma. Clin. Cancer Res. 2017, 23, 6759-6763. (145) Davis, I.; Liu, A. What is the tryptophan kynurenine pathway and why is it important to neurotherapy? Expert Rev. Neurother. 2015, 15, 719-721. 146) Ribas, A.; Hodi, F. S.; Callahan, M.; Konto, C.; Wolchok, J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N. Engl. J. Med. 2013, 368, 1365-1366. (147) Morrissey, K. M.; Yuraszeck, T. M.; Li, C. C.; Zhang, Y.; Kasichayanula, S. Immunotherapy and Novel Combinations in Oncology: Current Landscape, Challenges, and Opportunities. Clin. Transl. Sci. 2016, 9, 89104. (148) Gyawali, B.; Prasad, V. Drugs that lack single-agent activity: are they worth pursuing in combination? Nat. Rev. Clin. Oncol. 2017, 14, 193. (149) Mokhtari, R. B.; Homayouni, T. S.; Baluch, N.; Morgatskaya, E.; Kumar, S.; Das, B.; Yeger, H. Combination therapy in combating cancer. Oncotarget 2017, 8, 38022-38043. (150) Gieling, R. G.; Parker, C. A.; De Costa, L. A.; Robertson, N.; Harris, A. L.; Stratford I. J.; Williams K. J. Inhibition of carbonic anhydrase activity modifies the toxicity of doxorubicin and melphalan in tumour cells in vitro. J. Enzyme Inhib. Med. Chem. 2013, 28, 360-369. (151)

Do, M. T.; Kim, H.G.; Choi, J. H.; Jeong, H. G. Metformin induces microRNA-34a to downregulate the

Sirt1/Pgc-1alpha/Nrf2 pathway, leading to increased susceptibility of wild-type p53 cancer cells to oxidative stress and therapeutic agents. Free Radic. Biol. Med. 2014, 74, 21-34. (152) Issa, J.P.; Garcia-Manero, G.; Huang, X.; Cortes, J.; Ravandi, F.; Jabbour, E.; Borthakur, G.; Brandt, M.; Pierce, S.; Kantarjian, H. M. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer. 2015, 121, 556-561.


Page 95 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table of Contents Graphic


Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22


Page 96 of 135

Page 97 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43



Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20


Page 98 of 135

Page 99 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42



Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51


Page 100 of 135

Page 101 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50



Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17


Page 102 of 135

Page 103 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48



Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36


Page 104 of 135

Page 105 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51





Page 106 of 135

Page 107 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43



Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42


Page 108 of 135

Page 109 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31



Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48


Page 110 of 135

Page 111 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60





Page 112 of 135

Page 113 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60





Page 114 of 135

Page 115 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35





Page 116 of 135

Page 117 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59





Page 118 of 135

Page 119 of 135


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment



Page 120 of 135

Page 121 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50



Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21


Page 122 of 135

Page 123 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59



Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43


Page 124 of 135

Page 125 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46





Page 126 of 135

Page 127 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35





Page 128 of 135

Page 129 of 135 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43



Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27


Page 130 of 135

Page 131 of 135





Page 132 of 135

Page 133 of 135



Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52


Page 134 of 135

Page 135 of Journal 135 of Medicinal Chemistry 1 2 3 4 5 6


A Survey of the Structures of US FDA Approved Combination Drugs

Recommend Documents