Lead-like Drugs: A Perspective - Journal of Medicinal Chemistry (ACS

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Lead-like Drugs: A Perspective Miniperspective Brian Raymer* and Samit K. Bhattacharya* Medicine Design, Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States

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S Supporting Information *

ABSTRACT: Lead-like drugs, or drugs below molecular weight 300, are an important and sometimes overlooked component of the current pharmacopeia and contemporary medicinal chemistry practice. To examine the recent state-of-the-art in lead-like drug discovery, we surveyed recent drug approvals from 2011 to 2017 and top 200 prescribed medications, as well as provide case studies on recently approved lead-like drugs. Many of these recent drugs are close analogs of previously known drugs or natural substrates, with a key focus of their medicinal chemistry optimization being the choice of a low molecular weight starting point and maintaining low molecular weight during the optimization. However, the identification of low molecular weight starting points may be limited by the availability of suitable low molecular weight screening sets. To increase the discovery rate of leadlike drugs, we suggest an increased focus on inclusion and prosecution of lead-like starting points in screening libraries.

In small proportions we just beauties see, And in short measures life may perfect be.

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Ben Jonson. From Underwoods (1640): “To the Immortal Memory of That Noble Pair, Sir Lucius Cary and Sir Henry Morison”

INTRODUCTION Lead-like drugs, or drugs below molecular weight (MW) 300, are an important and sometimes overlooked component of the current pharmacopeia and contemporary medicinal chemistry practice. 1,2 In 2011, Walters and colleagues collated physicochemical properties of approved drugs across a 50year span. They found typical molecular weight ranges of approved drugs as 300−360 during the earliest time period (1959−1964), with a trend upward over time to 360−440 for the most recent time period (2005−2009). Taken together, it is reasonable to conclude that on average, the molecular weight of drugs typically falls within the range of 300−440. The molecular weight boundary of 300 for lead-like drugs also conveniently coincides with the molecular weight criteria of the rule-of-three (Ro3), although that value is focused on fragment selection for fragment-based drug discovery.3 Given these ranges and trends in molecular weight, we propose that drugs below a molecular weight of 300 can be considered atypical and use this criteria as an upper boundary for lead-like drugs.4 To examine the recent state-of-the-art in lead-like drug discovery, we surveyed drug approvals [by Food and Drug Administration (FDA) and European Medicines Agency (EMA)] between 2011 and 2017 (Figure 1; see Supporting © XXXX American Chemical Society

Figure 1. Number of new small molecule drug approvals and highly prescribed drugs, binned by molecular weight ranges: top 200 U.S. prescribed drugs in 2014 (red bars); drugs approved from 2011 to 2016 (blue bars); drugs approved in 2017 (green).

Information for the full list of drugs), excluding drugs above MW 2000. We also analyzed a list of the top 200 prescribed medications (branded and generic) from 2014 U.S. prescription data.5 The figure highlights the number of lead-like drugs recently approved and, moreover, the long-term success of lead-like drugs based on prescription levels of the top 200 prescribed medications. During 2011−2016, 25 of 146 recent drug approvals (17%) were below the typical molecular weight range of 300−440. As to the top 200 prescribed medications, 57 of the 160 low molecular weight drugs had a molecular Received: March 13, 2018

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DOI: 10.1021/acs.jmedchem.8b00407 J. Med. Chem. XXXX, XXX, XXX−XXX

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Table 1. Approved Drugs (2011−2017) Selected for Case Studiesa name

MW

clogP

PSA

po dose (mg)

KD, Ki, EC50, IC50, MIC50; (LE)b

1 2 3 4 5 6 7

tavaborole crisaborole ataluren vortioxetine edaravone tasimelteon lorcaserin

152 251 284 298 174 245 196

1.2 2.6 3.7 4.9 1.3 1.9 3.2

29.5 62.5 76.2 40.6 32.7 38.3 12

topical topical 700 10 60, iv 20 10

IC50 = 1 μM (0.78) IC50 = 0.5 μM (0.47) ICmax = 3 μM (0.38) Ki = 15 nM (0.53) EC50 = 10 μM (0.56) Ki = 0.35 nM (0.74) EC50 = 8 nM (0.88)

8 9 10 11 12

brivaracetam tipiracilg pomalidomide pitolisant dimethyl fumarate migalastat pirfenidone teriflunomide eslicarbazepineh

212 243 273 296 144

1 −0.2 −0.2 4.8 0.8

63.4 89.1 109.6 12.5 52.6

25 6.14 4 18 120

163 185 270 296

−1.4 2.4 2.1 1.5

93 22 73.1 72.6

123 267 14 800

IC50 IC50 IC50 IC50

compound

13 14 15 16

Vd (L)

T1/2 (h)

urine excretion (%)f

target class

2−6 66 4.5−6 1−4 11

50 59 70−90 80 92

IC50 = 100 nM (0.66) Ki = 20 nM (0.68) IC50 = 3 μM (0.4) EC50 = 1.5 nM (0.62) IC50 = 10 μM (0.72)

lowe 2600 18.5 56−126 CSF, CNSc 35d 333 62−138 lowe 53−73

enzyme enzyme unknown GPCR unknown GPCR GPCR

9 2 10 10−12 1

95 27 73 63 16

transporter enzyme multiple GPCR unknown

830 μM (0.42) 1.6 mM (0.30) 0.3 μM (0.49) 30 μM (0.35)

77−133 59−71 11 61d

3−5 3 18−19 d 13−20

77 80 23 90

enzyme enzyme enzyme ion channel

= = = =

a

po dose, Vd, T1/2, and % urine excretion taken from FDA or EMA product labels. bLigand efficiency (LE) for each drug was calculated using corresponding primary potency data in an in vitro assay described in the literature. cDistribution to CSF and CNS described. dBased on 70 kg body weight. eBased on no or moderate distribution to red blood cells and high plasma protein binding. fPercent urine excretion of parent and/or metabolites. gAs part of a combination. hMeasurements of parent drug.

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CASE STUDIES: DRUGS DERIVED FROM LEAD-LIKE SCREENING EFFORTS Tavaborole (1, Kerydin).

weight below 300, accounting for 36% of highly prescribed low molecular weight drugs. Of note, the large proportion of approved drugs above molecular weight 440 from 2011 to 2016 differs from the small proportion of drugs above molecular weight 440 represented in the top 200 prescribed drugs. The relative proportions of approved drugs less than molecular weight 300, molecular weight 300−440, and greater than molecular weight 440 differ considerably when comparing drugs approved in 2011−2016 and the top 200 prescribed drugs. A large proportion of drugs below molecular weight 300 are found in the top 200 prescribed drugs, while a higher proportion of drugs above molecular weight 440 are seen in the distribution of drugs approved between 2011 and 2016. Many of the top 200 prescribed low molecular weight drugs have been on the market for a long period of time; it will be interesting to observe how the molecular weight distribution of highly prescribed drugs evolves over time given the molecular weight distribution of recent approvals. For the year 2017, the recent trend of larger proportion of higher molecular weight drugs continues as 18/28 FDA approved drugs have molecular weight of >440 while 3/28 have molecular weight of 10 and an unbound efficacious concentration (Ceff) of > 1 μM fall into a property space of MW < 300 and higher polarity (clogP < 2.5).79 Recommendations and Considerations. Ensure Use of Screening Sets below MW 300. Lead-like starting points are key to the discovery of lead-like drugs. However, recent analyses of commercially available screening compounds observed a median molecular weight of 387 with a median absolute deviation of 78, indicating that a large portion of commercially available screening sets would not cover chemical space below molecular weight 300.80 This implies that many screening efforts likely may not lead to the identification of hits below molecular weight 300, a range representing approximately half of human drug−target pairs. Fortuitously, with the increased focus on fragment-based drug discovery, there are an increasing number of commercially available lead-like starting points.81−83 Lead-like starting points have also been used to identify adipocyte differentiation promoters through phenotypic screening and fragment-based chemical proteomics, providing lead-like starting points for optimization.84 Related to the discovery of lead-like drugs is the “medicinal chemist’s eye”, discussed in a comparative hit triage across many medicinal chemists.85 Namely, this investigation showed that medicinal chemists are relatively biased and differentiated in their evaluation of hit lists and hit triage. When applied to lead-like drug discovery, there may be a bias at the initial stages of screening that eliminate hits too soon based on molecular weight. It is reassuring to see that in the 16 examples included in this review, diverse target classes such as enzymes, GPCRs, ion channels, and transporters are represented. Additionally recent investigations of cryptic and secondary pockets86−88 may extend the target space of lead-like compounds to less

eslicarbazepine acetate) was shown to have the highest sodium channel inhibitory activity in vitro and in vivo. Although no crystal structure of the human sodium channel receptor has been solved, subtype nonselective sodium channel modulators such as eslicarbazepine (16c) are hypothesized to bind to an intracellular site within the sodium channel pore.

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DISCUSSION Inspection of the of the 28 of 174 lead-like drugs approved between 2011 and 2017 (see Supporting Information) reveals a property profile that falls between the “rule-of-three” and “rule of five” (Figure 2). For instance, 21 of 28 drugs below 300 MW have calculated log P values of 3 or less, 20 of 28 have three or less hydrogen bond donors, and 18 of 28 have three or less hydrogen bond acceptors. When viewed through the “ruleof-five” lens, only 1 of 28 drugs is an outlier with six hydrogen bonds.58 Additionally, all the lead-like drugs from 2011 to 2017 have total polar surface areas below 125 Å and rotatable bond counts below 10, compliant with property ranges preferable for oral bioavailability.59 There are three common themes that emerge when considering the selected case studies of recently approved drugs below molecular weight 300. First, a portion of the list such as tavaborole, crisaborole, and ataluren originate from screening efforts using lead-like libraries. Second, a large portion of the recently approved drugs are based on medicinal chemistry optimization or derivatization of known lead-like drugs or natural products. For instance, lorcaserin is a conformationally restricted analog of known serotonergic scaffolds, tasimelteon is related to known melatonin receptor agonists, and pomalidomide is a close structural analog of thalidomide. Taken together, the molecular weight of the medicinal chemistry starting point has a strong influence on the molecular weight of the approved drug.60,61 Third, repurposed drugs (dimethyl fumarate, pirfenidone) and active metabolites make up a small but significant portion of the recently approved lead-like drugs. Of note, while the lead-like drugs from the case studies have a range of potency values (Table 1), 11 of 15 have ligand efficiency values above the typical drug (0.45), correlating to high potency for each atom of the drug.62 Lead-like ADME and Toxicity. Lead-like drugs do not differ significantly in physicochemical properties of known drugs. In the case studies included, clogP and polar surface areas are typical of successful, orally bioavailable drugs (see Table 1).63 As a consequence of low molecular weight, the ligand efficiencies (LE) of these drugs are on the higher end of the range. However, the dose ranges of these drugs are within the ranges of historic drugs.64 To investigate ADME implications of molecular weight further, we analyzed data from a collection of 105 drugs of various molecular weights.65 We found that 76% of drugs with less than 300 MW had human oral bioavailability greater than 90% while only 53% of drugs with 300−440 MW and 42% of drugs with MW above 440 had human oral bioavailability greater than 90%. This trend of increased bioavailability of lead-like compounds may correspond to previously noted relationships of solubility and permeability to molecular weight. Specifically, solubility tends to decrease in relation to increased molecular size, and low molecular weight compounds may have both paracellular and transcellular paths to absorption.66−69 Likewise, an analysis of a diverse set of 47 018 compounds by Johnson and colleagues demonstrated the predictive value F

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represented target classes through allostery, induced fit, or other mechanisms. Emphasize MW-Neutral, MW-Limited Medicinal Chemistry. Molecules at or below molecular weight 300 may typically be viewed as hits that need to be advanced through medicinal chemistry optimization to provide drugs, whether through potency or property optimization. However, a comparison of molecular weight ranges of starting compounds to optimized compounds in the monoamine GPCR family identified a median change in molecular weight of 30 (mean change 50) in optimization of starting compounds below molecular weight 300. 89 This implies that optimized compounds can have similar molecular weights compared to their lead-like starting points. The analysis identified ion channels and transporters, in addition to monoamine GPCRs, as protein target classes associated with lower molecular weight ligands. Supporting this, clinical candidates in the ion channel target class have significantly lower molecular mass on average. This implies that starting compounds in certain target classes may be more amenable to optimization efforts toward clinical candidates that retain a low molecular weight.90 Additionally, the identification of binding pockets with lower surface area may also indicate the opportunity for lead-like drug discovery efforts.91 The implementation of lead-like screening strategies is feasible, and lead-like medicinal chemistry optimization efforts, while challenging, may yield desired results. High concentration fragment screening using biochemical assays has demonstrated utility, providing sensitive hit identification with an acceptable number of artifacts due to the high concentration.92 Fragment-based screening in biochemical assays was shown to be suitable for the identification of serine protease and metalloprotease targets and can reduce protein requirements when compared to SPR and NMR fragmentbased screening techniques.93 Keeping molecular weight low during fragment to lead medicinal chemistry efforts can be difficult. An analysis of 2015 and 2016 fragment to lead medicinal chemistry publications by Johnson and colleagues shows that out of 55 publications with hits less than molecular weight 300, only 6 resulted in leads with less than molecular weight 300.94,95 Application of medicinal chemistry strategies such as conformational restriction, heavy atom substitution, and truncation that maintain or reduce molecular weight is advisible to investigate, while strategies such as growth into additional pockets, fragment linking, or appending solubilizing groups may be contraindicated. Further work is needed to determine how and when lead-like screening and medicinal chemistry strategies are deployed. Evaluate Biological and Clinical Options. Finally, sources of drugs without the need of large-scale screening or extensive medicinal chemistry efforts should not be ignored. Metabolites of known drugs, biological investigations of natural products, and clinically driven repurposing of known drugs have all resulted in new drug approvals.

like space may include reduced toxicity and improved absorption and clearance. However, the identification of low molecular weight starting points may be limited by the availability of suitable low molecular weight screening sets. To increase the discovery rate of lead-like drugs, we suggest an increased focus on inclusion of lead-like starting points in screening libraries. While it may not be possible to generate clinical candidates and drugs that are lead-like in all cases, historic and recent drug approvals indicate that this area is ripe for further pursuit.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b00407. List of FDA and EMA approved drugs from 2011 to 2017 with physicochemical properties and Smiles (CSV)

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AUTHOR INFORMATION

Corresponding Authors

*B.R.: e-mail: [email protected]. Current Address: Alkermes, Inc. 852 Winter Street, Waltham, Massachusetts 02451. *S.K.B.: e-mail: samit.k.bhattacharya@pfizer.com. ORCID

Samit K. Bhattacharya: 0000-0002-0948-4254 Notes

The authors declare no competing financial interest. Biographies Brian Raymer earned a B.A in Chemistry from St. Olaf College (Northfield, MN) and then joined the Process Development group at Pfizer (Groton, CT). He then moved to Harvard University and obtained his Ph.D. with Prof. David A. Evans working on synthetic routes toward a marine toxin, azaspiracid. In 2004, he joined the Global Discovery Chemistry department at Novartis (Cambridge, MA) working on small molecule projects in the diabetes, metabolism, and cardiovascular disease areas as well as peptide, polymer, and antibody−drug conjugate projects as part of the Chemical Biology department. In 2013 he moved to Pfizer (Cambridge, MA) as a medicinal chemistry and research project leader in Medicinal Design, contributing to two clinical candidates including a ketohexokinase inhibitor currently in phase 2 clinical trials. Samit K. Bhattacharya did his undergraduate work in Organic Chemistry at Jadavpur University, Calcutta, India, and earned his Ph.D. at University of Pennsylvania, Philadelphia, PA, under the tutelage of Professor Jeffrey Winkler working on the total synthesis of anticancer drug paclitaxel (Taxol). Thereafter he moved to Columbia University, NY, as a Postdoctoral Fellow with Professor Samuel Danishefsky, working on the total synthesis of anticancer agent eleutherobin and ganglioside GM-1. In 1999, he joined the Oncology group in Pfizer, Groton, CT, as a medicinal chemist and then moved onto the Cardiovascular and Metabolic Diseases group. Samit has contributed to multiple clinical candidates across these two therapeutic areas. Samit is currently in the Inflammation and Immunology group located in Cambridge, MA.

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CONCLUSIONS Compounds below molecular weight 300 represent a fruitful area of drug research with a number of recent drug approvals occurring in this space. Many of these recent drugs are close analogs of previously known drugs or natural substrates, with a key focus of medicinal chemistry optimization being the choice of a low molecular weight starting point and maintaining low molecular weight during the optimization. Advantages of lead-

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ACKNOWLEDGMENTS The authors are indebted to Drs. David Price, Markus Boehm, John Litchfield, Fabien Vincent, Phil Carpino, and Manthena Varma for critically reviewing the manuscript and providing G

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invaluable suggestions. The authors also thank the ACS reviewers for their thoughtful suggestions.

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ABBREVIATIONS USED MW, molecular weight; PSA, polar surface area; Ro3, rule of three; LE, ligand efficiency; DHODH, dihydroorotate dehydrogenase; NSAID, nonsteroidal anti-inflammatory drug; HBD, hydrogen bond donor count; SERT, serotonin transporter; ALS, amyotrophic lateral sclerosis; ADME, absorption, distribution, metabolism and excretion

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