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Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry Tanaji T. Talele* Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, New York 11439, United States S Supporting Information *

ABSTRACT: The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the pKa of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe−Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.

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A SYNOPSIS OF NATURAL PRODUCTS CONTAINING THE GEM-DIMETHYL MOIETY Natural products and their semisynthetic/synthetic derivatives have served as a consistent source of valuable new drug leads for centuries.1−3 Since ancient times, humans have relied on the treatment of diseases with plants and/or plant extracts.2 For example, cinchona bark has long been used to treat fever and willow bark has efficacy as an anti-inflammatory and analgesic. In general, natural products display an exceptionally wide range of structural diversity, dense arrays of functional groups, stereochemical complexity, and a large number of sp3hybridized centers, features that can lead to an enhanced three-dimensional molecular diversity and thus to a unique molecular shape.4,5 A unique feature of many of these natural products is the presence of a gem-dimethyl group that is directly connected either to an oxygen atom or to a −C−O functionality, as highlighted in red in Figures 1−3. A bibliographical search in the SciFinder,6 using “gem-dimethyl” as the search key, revealed 439 articles as of August 10, 2017. Representatives of numerous known gem-dimethyl-containing natural products and their synthetic analogues (1−22),7,8 categorized based on their source (plant, microbe, or marine organism) are shown in Figures 1−3.9−30 The purpose of this article is to provide an insight into how medicinal chemists have recognized the importance of a gemdimethyl group and have successfully incorporated this group into biologically active small molecules as a way to enhance a specific therapeutic effect. This strategy can be traced back to © 2017 American Chemical Society

the 1920s when the gem-dimethyl-containing penicillins were accidentally isolated by Alexander Fleming from the fungus Penicillium notatum. Interestingly, about 64% of the new small molecule drugs introduced between 1981 and 2010 were modified natural products.2 Currently, there are 12 gemdimethyl-containing compounds in clinical trials, about 30 in preclinical development, and at least 51 drugs, which amounts to 3.7% of the total number of U.S. FDA approved drug molecules (1391) (based on DrugBank version 5.0 database31 search on May 25, 2017, and examples described in this article).

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PHYSICOCHEMICAL, STRUCTURAL, AND BIOLOGICAL PROPERTIES IMPARTED BY A GEM-DIMETHYL GROUP A gem-dimethyl group, being electronically neutral as well as lacking polarity, can be considered as two small lipophilic lobes projecting out of the bioactive conformation of the molecule. Importantly, however, these small lipophilic lobes can have a significant bearing on several desirable pharmacodynamics (PD), structural, toxicity, and drug metabolism and pharmacokinetics (DMPK) properties that are required to develop a successful drug as illustrated in Figure 4 and briefly described in the following sections. Impact of the gem-Dimethyl Group on Pharmacodynamics, Structural, and Toxicity Properties. Insertion of a Received: February 27, 2017 Published: August 29, 2017 2166

DOI: 10.1021/acs.jmedchem.7b00315 J. Med. Chem. 2018, 61, 2166−2210

Journal of Medicinal Chemistry

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Figure 1. Structures of representative plant-derived natural and semisynthetic products (1−13) containing the gem-dimethyl group.

Impact of the gem-Dimethyl Group on DMPK Profile. Phase 1 and phase 2 metabolic stability is one of the key parameters in establishing the bioavailable amount and duration of action of an administered drug. One of the many strategies to delay or prevent metabolic degradation of labile functional groups in a drug molecule is to install a gem-dimethyl group next to the primary alcohol leading to masking of the alcohol group from oxidizing enzymes with simultaneous prevention of oxidation of the methylene carbon.32,33 Moreover, this molecular modification also prevents potential phase 2 conjugation of the alcohol group as a consequence of steric crowding.32,33 Increased chemical and plasma stability of an unstable functional group can be achieved by insertion of a gemdimethyl steric bulk next to the labile groups.34,35 The gemdimethylation at the benzylic carbon can considerably prevent oxidative metabolism.36−39 The three interacting methyl groups in an o-hydroxydihydrocinnamic acid promoiety imposes a conformational restriction that significantly increases the rate of cyclization (lactonization) and subsequent release of pharmacologically active drug.40,41 Incorporation of a gem-dimethyl group can moderately modulate the pKa of nearby acidic and basic functional groups to modify plasma membrane permeability.42,43 The gem-dimethylation at the methylene precursor increases molecular lipophilicity by ∼1 log10 unit, which can

gem-dimethyl group at the methylene of bioactive compounds can considerably modify the rotational barriers about a rotatable bond, enforce a bioactive conformation, and provide favorable van der Waals interactions with the binding site of the target protein. Furthermore, the open chain gem-dimethyl quaternary carbon considerably reduces the conformational flexibility and facilitates entropically favorable binding to the target receptor. Consequently, the gem-dimethyl group substitution may lead to increased binding affinity toward the target protein as long as it enforces a bioactive conformation. Further, a gem-dimethyl group can also contribute to increased selectivity and extended target engagement. Introduction of symmetry at the chiral center tends to simplify molecular complexity, synthesis, and characterization and ensuing candidate drug development efforts. To achieve this goal, symmetry can be induced by the addition of the second methyl group at monomethylated chiral centers in bioactive compounds. Installation of a gem-dimethyl group α to the carboxylate moiety can significantly reduce reactivity of the glucuronide ester metabolite and subsequent idiosyncratic toxicity. Additionally, insertion of a gem-dimethyl group in a planar tricyclic ring structure can mitigate genotoxic effects (Figure 4). 2167



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Figure 2. Structures of representative microbe-derived natural products (14−19) containing the gem-dimethyl group.

Figure 3. Structures of representative marine-derived natural products (20−22) containing the gem-dimethyl group.

infections. One of the first fermentation-derived β-lactam antibiotics was 23 (benzylpenicillin/penicillin G, Figure 5). To improve the chemical/enzymatic stability and activity against resistant bacterial strains, several new chemically modified penicillin antibiotics were subsequently synthesized.53 This review will only discuss a representative group of β-lactams such as 24 (methicillin), 25 (ampicillin), 26 (amoxicillin), and a third generation example, a gem-dimethyl substituted aminothiazole oxime (highlighted in red) derivative, 27 (ceftazidime), as shown in Figure 5. β-Lactam antibiotics irreversibly acylate a serine residue in the active site of the bacterial transpeptidase enzyme (penicillin binding proteins/PBPs), whose activity is critical for bacterial cell wall synthesis.54 The gem-dimethyl

contribute to increased brain permeability.44,45 Insertion of a gem-dimethyl group in bioactive molecules can impact number of other PK parameters such as increased half-life,46,47 area under the curve (AUC),32 bioavailability,46,48 CNS exposure,44,45 decreased plasma clearance,39,46−49 CYP450 inhibition,33,38 pregnane X receptor (PXR) activation,38,50 and Pglycoprotein (P-gp) efflux ratio (Figure 4).33,51,52

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PHARMACODYNAMICS CONTRIBUTION OF A GEM-DIMETHYL GROUP To Achieve Efficient Target Engagement, Potency, and Selectivity. β-Lactam Antibiotics (23−28). Penicillin antibiotics have been widely used in treating bacterial 2168



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Figure 4. Impact of a gem-dimethyl group on pharmacodynamics, structural, toxicity, and DMPK properties.

Figure 5. Structures of β-lactam antibiotics 23−28.

group (Figure 5) and via intermolecular van der Waals interactions with the side chain of Tyr707 of PBP1.55 The gem-dimethyl substituted aminothiazole oxime moiety present in the antibiotic, 27, demonstrated enhanced acylation efficiency toward the active site serine residue of PBP, a result attributed to favorable hydrophobic interactions between the gem-dimethyl group and hydrophobic aromatic wall created by Tyr503, Tyr532, and Phe533 residues.56 Since metallo-βlactamase is responsible for bacterial resistance to penicillins, the gem-dimethyl substituted irreversible metallo-β-lactamase inhibitors such as 28 (sulbactam) were developed for use in combination with certain β-lactams (Figure 5). The gem-

Figure 6. Structure of monobactam antibacterial drug 29.

group in compounds 24−26 has been shown to engage in intramolecular van der Waals interactions with the side chain R 2169



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Figure 10. Structure of HCV NS3/4A protease inhibitor 37.

Figure 7. Structures and antibacterial efficacy of siderophoreconjugated monobactam antibiotics 30 and 31 and a positive reference monobactam 29.

Figure 11. Structures and in vitro potency of HIV-1 integrase inhibitors 38−41.

appears that the antibacterial activity of 29 is exerted through inhibition of PBP3 in Gram-negative bacteria. Removal of a gem-dimethyl substituent in a structurally related monobactam siderophore antibiotic, 30 (Figure 7),60 eliminated the antibacterial efficacy against P. aeruginosa and produced a 10fold reduction in acylation efficiency toward the active site serine residue. This observation was rationalized based on analysis of the crystal structure of 29 bound in complex with PBP3 from P. aeruginosa (PDB code 3PBS), which indicated stabilization of the gem-dimethyl group through hydrophobic interactions with an aromatic wall formed by Tyr503, Tyr532, and Phe533.56 Siderophore-Conjugated Monobactam Antibiotic 31. This class of antibiotics is stable in the presence of metallo-β-

Figure 8. Structures of dehydropeptidase I inhibitor 32 and antibiotic 33.

dimethyl group of metallo-β-lactamase inhibitors forms the hydrophobic interactions with the side chains of active site residues Trp64 and Val67.57 Monobactam Antibiotic 29 (Aztreonam/Cayston). In 1986, the arginine salt of aztreonam (29/SQ 26776)58 was approved to treat bacterial infections (Figure 6). In 2010, the U.S. FDA approved the lysine salt of aztreonam for use as a nebulized inhalation to improve respiratory symptoms in cystic fibrosis patients infected with Pseudomonas aeruginosa.59 It

Figure 9. Structures, in vitro potency, and DMPK properties of antitubercular compounds 34−36. 2170



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Figure 12. Structures, in vitro potency, and DMPK properties of RSV fusion protein inhibitors 42−45.

Figure 13. Structures and in vitro potency of plasmepsin inhibitors 46−50.

Figure 14. Structures and in vitro potency of AR antagonists 51−55. a Reduction in luciferase activity is a desirable end point. bPSA: prostate specific antigen.

lactamases and readily penetrates across the membrane of susceptible bacteria, respectively contributed by monobactam and iron-chelating siderophore (highlighted in blue) structural features. Insertion of a gem-dimethyl moiety on the aminothiazole oxime (highlighted in red) region of the monobactam siderophore in 30 produced 31, with a significant increase in the efficacy against P. aeruginosa, as well as a 10-fold increase in

Figure 15. Structures and in vitro potency of IGF-1R inhibitors 56− 59.

acylation efficiency (Figure 7).60 In addition to showing antibacterial profile superior to the U.S. FDA approved 29, 31 also had an excellent pharmacokinetic profile.60 2171



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Figure 16. Structures, in vitro potency, and physicochemical and PK properties of MTH1 inhibitors 60−62.

Figure 20. Structures and in vitro potency of MMP inhibitors 74 and 75.

Figure 17. Structures, in vitro potency, and PK profiles of SIRT inhibitors 63−65.

Figure 18. Structures and in vitro potency of ICMT inhibitors 66−68.

Figure 21. Structures and in vitro potency of HSP90 inhibitors 76− 79.

metabolic degradation of 33 to inactive compounds (Figure 8).61,62 32 binds to DHP-I in a similar fashion to that of substrate 33. Moreover, the conformation of 32 is also nicely juxtaposed for attack by the active site zinc-bound water/ hydroxide nucleophile to form the tetrahedral intermediate. However, a tetrahedral intermediate is resistant toward cleavage of the amide bond as a consequence of tight binding of the gemdimethylcyclopropane moiety to the side chains of Trp25 and Tyr68.63,64 Consequently, 32 functions as an inhibitor of renal DHP-I. Antitubercular Compound 36. An increased rate of multidrug resistant and extensively drug resistant tuberculosis has augmented the stimulus to create new classes of

Figure 19. Structures and in vitro potency of MMP inhibitors 69−73.

Dehydropeptidase I (DHP-I) Inhibitor 32 (Cilastatin). Compound 32 is a reversible inhibitor of renal enzyme DHP-I that is used in combination with the antibiotic 33 (imipenem/ primaxin) to increase the in vivo stability of 33, resulting in a longer duration of antibacterial efficacy by preventing the 2172



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Figure 22. Structures, in vitro potency, and PK profiles of HSP90 inhibitors 80 and 81.

Figure 23. Structures, in vitro potency, and DMPK profiles of PI3K inhibitors 82−85.

(data not shown) and pure trans (35) compounds had comparable antitubercular potency but different metabolic stability, being poor for the former. Subsequently, 35 was subjected to SAR optimization by exploration of hydrophobic space surrounding the 4-position of the cyclohexane moiety. Installation of a gem-dimethyl group (compound 36) led to increased lipophilicity and gave a 10-fold increase in potency compared to 35. Additionally, this modification removed the complexity arising from the cis/trans isomerism of 34. 36 also exhibited a favorable PK profile (Figure 9) and showed potent oral efficacy in a mouse model of acute TB (a 25 mg/kg oral dose produced a 2.6 log lung colony forming unit reduction).65 Hepatitis C Virus (HCV) NS3/4A Protease Inhibitor 37 (Boceprevir/Victrelis). Compound 37 (SCH 503034)66 is the first U.S. FDA approved HCV NS3/4A protease inhibitor (Figure 10); however, it was voluntarily withdrawn from the U.S. market as a result of availability of other superior treatment options. One of the major structural modifications leading to 37 was the introduction of a gem-dimethylcyclopropanoproline P2 moiety as a leucine surrogate. The improved potency of 37 as compared to the corresponding leucine substituted analogue

Figure 24. Structures and in vitro potency of RXR selective compounds 86−88.

antitubercular drugs. Toward this goal, Kondreddi and coworkers65 optimized a cell-based screening hit into a highly potent, indole-2-carboxamide scaffold as antitubercular compounds. One analogue, 34, that had a promising antitubercular potency and metabolic stability (Figure 9) is a mixture of cis and trans isomers (38:62). It was observed that the pure cis 2173



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Figure 25. Structures of retinoids 89−91.

Figure 26. Structure, in vitro potency, and CYP450 inhibition data for PI3Kδ inhibitor 92. Figure 30. Structures and in vitro potency of renin inhibitors 100− 102.

Figure 27. Structure of 93.

Figure 31. Structures and in vitro potency of HMG-CoA reductase inhibitors 103−105.

Figure 28. Structures and in vitro potency of nAChR antagonists 94− 97. aPotency relative to (rac) 94.

Figure 29. Structures of 5-HT1A receptor agonists 98 and 99.

Figure 32. Structures and in vivo potency of potassium ion channel openers 106−111. 2174



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Figure 33. Structures, in vitro potency, and PK profiles of LXR agonists 112−115. aHuman whole blood ABC transporter family A1 induction.

Figure 34. Structures, in vitro potency, and PK profiles of NHE1 inhibitors 116 and 117.

Figure 36. Structure, in vitro potency, and liver microsomal profile of CCR1 antagonist 121. aMIP: macrophage inflammatory protein.

is a consequence of a favorable interaction between the gemdimethylcyclopropanoproline P2 moiety and the side chain of Ala156 (PDB code 3LOX).64,66

HIV-1 Integrase Inhibitor 41 (Raltegravir/Isentress). HIV-1 integrase serves as an important therapeutic target to

Figure 35. Structures of mTOR inhibitors 118−120. 2175



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Figure 37. Structures of MDP 122 and its analogues 123 and 124.

dine-4-carboxamides as early lead compounds, with variation at the C2-position of the dihydroxypyrimidine core (Figure 11). A C2-dimethylaminomethyl substituent led to 38, which had an acceptable inhibitory potency. The branching of the methylene linker with a monomethyl group resulted in compounds with increased potency, 39. Interestingly, insertion of a gem-dimethyl group at the methylene linker yielded inhibitor, 40, with significantly increased cell-based potency. Since any modification to the gem-dimethyl substituent produced a significant loss in potency, it is possible that this group is playing a critical role in the antiviral activity of 40.67 Having established the gemdimethyl group as an optimal C2-substituent of compounds in the dihydroxypyrimidine series, Summa and colleagues68 reported a related N-methylpyrimidone scaffold with similar or enhanced activity in the HIV-1 integrase assay, as exemplified by the U.S. FDA approved 41 (raltegravir, Figure 11). Moreover, 40 and 41, in the presence of 10% and 50% fetal bovine serum (FBS), were significantly more potent compared to 38 and 39, which may suggest a lower propensity to bind to the serum proteins.68 Human Respiratory Syncytial Virus (RSV) Fusion Protein Inhibitors 44 and 45. RSV is responsible for acute upper and lower respiratory tract infections in infants and young children. Zheng and co-workers36 developed novel RSV inhibitors based on a piperazinylquinoline scaffold that was derived from a similarity-based virtual screening of more than one million small molecules present in the Roche Smart library against known RSV fusion inhibitors. Optimization of lead compounds obtained from this library led to the identification of 42, with significantly enhanced cellular efficacy (Figure 12). Considering the benzylic carbon as a metabolic hot spot, these investigators inserted small alkyl groups at the benzylic carbon position. Insertion of a monomethyl group at the benzylic carbon yielded 43, which exhibited comparable potency to that observed for 42. However, gem-dimethyl substitution at the benzylic carbon resulted in 44, with a 3-fold increase in potency compared to 43. Also, 44 was reduced in complexity by removal of the stereocenter present in 43. Methylation of the primary amine head group gave 45, with cell-based efficacy that was comparable to that observed for 44. Since both 44 and 45 had excellent liver microsomal stability and PK profile, they

Figure 38. Structures, in vitro potency, and physicochemical properties of ITK inhibitors 125−128.

Figure 39. Structures, in vitro potency, physicochemical properties, and HLM clearance profiles of muscarinic M3 receptor antagonists 129−132.

treat HIV-1 infection. Since the active site of HIV-1 integrase contains divalent metal ions that are critical for catalysis, inhibitors of this enzyme should contain a metal chelating functionality such as diketo acid or a dihydroxypyrimidine. Pace and co-workers67 synthesized N-benzyl-5,6-dihydroxypyrimi2176



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Figure 40. Structures and in vitro potency of PDE4 inhibitors 133 and 134.

pocket of Plm II. Despite this insight, these investigators installed a symmetric gem-dimethyl group at the benzylic carbon to avoid chiral complexity. Moreover, the benzylic carbon can be made metabolically stable if modified to contain the gem-dimethyl group. The plasmepsin inhibitory data of compounds 46−49 suggest that the gem-dimethyl substitution is critical for potency (Figure 13). In addition, the gem-dimethyl substituted compounds significantly inhibited the growth of the 3D7 strain of Plasmodium falciparum. Finally, replacing a piperidine ring with a phenyl ring yielded 50, which was 9-fold more selective toward Plm IV compared to the human aspartyl protease, cathepsin D.70 Nonsteroidal Androgen Receptor (AR) Antagonists 51 (Nilutamide/Nilandron) and 55 (Enzalutamide/Xtandi). Castration-resistant prostate cancer is characterized by approximately 3- to 5-fold increase in expression of the AR gene.71 The first generation of AR antagonists produced partial agonism; therefore, to remove this pharmacological liability, there is a need to develop a second generation of AR antagonists to provide AR antagonism in cells that express high levels of AR.72 Toward this goal, Jung and co-workers73 synthesized AR antagonists that produced antagonistic action in the AR-upregulated castration resistant disease state, based on lead compound 51 (nilutamide, Figure 14). An early lead structure is exemplified by the gem-dimethyl substituted thiohydantoin ring system (52), which produced significant reduction not only in luciferase reporter activity but also in the down-regulation of prostate-specific antigen (PSA) levels. Removal of both methyl groups as in compound 53 or the inclusion of one methyl group (as in compound 54) at the C5position of the thiohydantoin ring resulted in a significant decrease in potency. Since the gem-dimethyl group proved

Figure 41. Structures, in vitro potency, and PK profile of cathepsin K inhibitors 135 and 136.

were considered suitable for further preclinical development as anti-RSV drugs.36 Plasmepsin Inhibitor 50. Digestive vacuole plasmepsins (Plm I, II, and IV) have been considered as antimalarial drug discovery targets. Genetic knockout studies have suggested a role for Plm IV in reducing hemozoin accumulation, resulting from impaired hemoglobin digestion.69 Jaudzems and coworkers70 selected a hydroxyethylamine scaffold (compound 46) as a starting lead to optimize selective plasmepsin inhibitors (Figure 13). X-ray cocrystal structure of 46-Plm II suggested that one methyl group is exposed to the polar environment and that a second methyl group is located within the hydrophobic

Figure 42. Structures, in vitro potency, and physicochemical properties of adenoviral protease inhibitors 137−142. aCPE: cytopathic effect. b PAMPA: parallel artificial membrane permeability assay. n.d.: not determined. 2177



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Figure 43. Structures and in vitro potency of PPARα agonists 143−147. NA: not active.

from adopting an agonist-like conformation (this was observed more so with the wild-type AR than with the mutant AR).75 55 received U.S. FDA approval in 2012 for the treatment of patients with metastatic castrate-resistant prostate cancer. Insulin-like Growth Factor 1 Receptor (IGF-1R) Inhibitor 59. The development of small molecule inhibitors of the IGF-1R signaling pathway has been hypothesized to be an effective strategy to treat cancer.76 Stauffer and colleagues77 reported the discovery of 56, an ATP competitive IGF-1R inhibitor with acceptable inhibitory activity, as well as selectivity over a panel of kinases (Figure 15).78 However, its oxidative Odebenzylated metabolite 57, while preserving the IGF-1R inhibitory action, was devoid of selectivity over related kinases. These results accentuated the role of the O-benzyl moiety in conferring selectivity. To overcome the metabolic liability of the benzylic carbon in 56, these investigators performed SAR studies that led to the discovery of (S)-58, with an IGF-1R inhibitory potency comparable to that of 56. A gain in IGF-1R inhibitory power of 1 order of magnitude was realized when a gem-dimethyl group was inserted in lieu of the methylene linker (compound (S)-59), as shown in Figure 15. Both (S)-58 and (S)-59 produced a kinase selectivity profile that was significantly better than that of 57.77 (S)-59 had good water solubility, showed high permeability under basic conditions through a parallel artificial membrane permeability (PAMPA) assay, and had no significant effect on drug metabolizing CYP450 isoforms (CYP3A4, CYP2D6, and CYP2C9).77 MutT Homolog 1 (MTH1) Inhibitor 62. MTH1 plays an important role in preventing insertion of oxidized purines into DNA through the hydrolytic cleavage of 8-oxo-dGTP and 2hydroxy-dATP to their corresponding monophosphates.79 Consequently, MTH1 is an important target for oncologic drug discovery. Subsequent work by Petrocchi and colleagues51 used a crystal structure and molecular modeling data to design a 2,4-disubstituted pyrimidine scaffold, exemplified by 60 (Figure 16). They installed a gem-dimethyl group on the C2position of the hydroxypropoxy substituent in 60 for two reasons: first to obviate the desolvation penalty of the ligand and second to occupy the lipophilic pocket of MTH1. These

Figure 44. Structures, in vitro potency, and PK profile of GPIIb/IIIa antagonist 148.

Figure 45. Steric restriction imposed by the α-aminoisobutyric acid.

beneficial, it was kept constant while performing SAR studies on the N1-phenyl ring. Ultimately, insertion of a 3-fluoro-4-Nmethylcarboxamide group onto the N1-phenyl ring (as in compound 55/MDV3100/enzalutamide) proved optimal (Figure 14).73 55 competitively binds to the ligand-binding domain of the AR and inhibits translocation of the AR to the nucleus, recruitment of AR cofactors, and AR binding to DNA.74 The role of the C5-gem-dimethyl group in 55 in conferring antagonism was verified by removal of this moiety, which led to an analogue that elicited undesirable agonistic activities against both wild-type and the F876L mutant of the AR.75 Docking and molecular dynamics simulations of 55 within the ligand binding domain of AR (wild-type and F876L mutant) suggested a steric interaction between the C5-gemdimethyl group and helix H12, which appeared to prevent H12 2178



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physiological pH. A cocrystal structure of 72 with truncated stromelysin indicated that the high potency of 72 resulted from hydrophobic interactions between one of the methyl groups of its gem-dimethyl moiety and the side chain of Val163.84 Pikul and colleagues85 also developed new MMP inhibitors bearing a plane of symmetry to avoid the complexities posed by chiral centers. To achieve this goal, they first developed the symmetric lead compound 74, showing a moderate inhibition of certain MMPs (Figure 20). Insertion of a gem-dimethyl substituent at the C5-position of the 1,3-piperazine ring led to compound 75 with improved MMP inhibition (Figure 20). The crystal structure of 75 and the truncated stromelysin complex (PDB code 1BQO) showed favorable van der Waals interactions between the gem-dimethyl group and the side chains of Val163 and Pro221, thus explaining the potencyenhancing nature of hydrophobic gem-dimethyl group in 75.85 Heat Shock Protein 90 (HSP90) Inhibitors (76−81). HSP90 serves as an anticancer drug target;86 therefore, Huang and colleagues87 started an HSP90 inhibitor development program with an optimized lead, 76, derived from an ATPbinding site focused library screening effort. 76 blocked the degradation of Her-2 and also inhibited HSP90 bioactivity at a low micromolar concentration (Figure 21). Installation of a gem-dimethyl group at the C6-position of the indolone ring led to compound 77, which was significantly more efficacious than 76 at inhibiting both Her-2 degradation and HSP90 bioactivity. An X-ray crystal structure of a compound related to 77 with the N-terminal domain of HSP90 indicated a significant displacement of the active site Leu107 residue from its original position due to the steric demands of the C6-gem-dimethyl group. Although 77 was a very potent compound, it was unsuitable for further development because of its (a) high lipophilicity, (b) poor aqueous solubility, (c) undetectable oral bioavailability, (d) lack of sufficient efficacy in mouse tumor xenograft models, (e) pyrrole and trimethoxyaniline metabolic liabilities, and (f) aniline ring producing a toxic and reactive quinone metabolite. Consequently, SAR optimization was conducted on 77 while keeping the optimized gem-dimethyl group constant. Specifically, 77 was modified by replacing the 3-methylpyrrole ring with the solubility-enhancing 3-trifluoromethylpyrazole ring and the planar trimethoxyaniline ring with a trans-4hydroxycyclohexylamine. These modifications produced 78, which had a lower in vitro potency but improved oral bioavailability and efficacy in mouse xenograft models compared to 77. While the amorphous form of 78 had good aqueous solubility (170 μM) at pH 7.4 and oral bioavailability, its crystalline forms showed only a limited solubility (6 μM) at physiological pH. To avoid further formulation development problems and to prepare a candidate suitable for both oral and parenteral administration, 78 was converted into the highly water-soluble (∼1 mg/mL at pH 4−6) glycine ester mesylate prodrug 79, which had reasonable inhibitory action in both Her-2 degradation and HSP90 bioactivity assays. It is of interest to note that 79 underwent rapid and complete hydrolysis to the parent molecule, 78. Compound 79, when administered orally, had excellent antitumor efficacy in the HT-29 colon tumor xenograft model.87 Shi and co-workers32 began a HSP90 inhibitor development program with the pyrrolopyrimidine scaffold that was considered suitable for improving the PK profile through modification of the solvent-exposed region. The optimized lead compound, 80, had a sterically unhindered propargyl moiety with a primary alcohol group. Steric crowding, adjacent to the

efforts led to 61, which increased MTH1 inhibition by an order of magnitude (Figure 16). A further increase in MTH1 inhibitory activity to the picomolar range occurred when a methyl group was installed at C5 on the pyrimidine ring to yield 62. Compound 62 showed an exceptionally low efflux ratio, a high aqueous solubility, a high free fraction in human plasma, a long plasma half-life, and no off-target activity at 1 μM when tested against 97 kinases from KinomeEdge panel of kinases. It also inhibited MTH1 in MTH1 overexpressing U2OS cells at nanomolar concentrations.51 Sirtuin (SIRT) Inhibitors 63 and 64. Recently, SIRT1 and SIRT2 have been evaluated as molecular targets for anticancer drug discovery.80 Consequently, Therrien and co-workers49 designed a novel tetrahydroindazole scaffold for exploration of SIRT1 and SIRT2 inhibition. Compound 63 was developed to show preferential inhibition of SIRT1 over SIRT2 (Figure 17). Substitution of a gem-dimethyl group at the 5-position of the tetrahydroindazole ring of 63 led to 64, which was as potent as 63 at inhibiting SIRT1 but lost selectivity over SIRT2. Moving a gem-dimethyl group from the 5- to the 4-position led to the regioisomer 65, which proved inactive against both SIRT1 and SIRT2 (Figure 17).49 Isoprenylcysteine Carboxyl Methyltransferase (ICMT) Inhibitor 68. The enzyme ICMT plays an important role in Ras localization and transformation in human cell-based models.81 Therefore, it is possible that small molecule ICMT inhibitors may be useful in treating certain types of cancers. Toward this objective, Judd and colleagues82 screened a library of compounds against human recombinant ICMT and identified a submicromolar ICMT inhibitory lead compound containing a gem-dimethyl tetrahydropyranyl scaffold. Subsequently, they determined the effect of a gem-dimethyl group on the tetrahydropyran ring (Figure 18). Compound 66, lacking a gem-dimethyl group on the tetrahydropyran ring, had moderate inhibitory action on ICMT. Insertion of a gemdimethyl moiety at the C2-position of the tetrahydropyran ring resulted in chiral compound 67, with a > 50-fold improvement in ICMT inhibitory efficacy. To eliminate chiral complexity, another gem-dimethyl group was installed at the C6-position of the tetrahydropyran ring, a modification that led to 68 and a further increase in ICMT inhibition efficacy. In addition, 68 was also cytotoxic against several cancer cell lines as evidenced from IC50 values ranging from 0.3 to >100 μM.82 Matrix Metalloprotease (MMP) Inhibitors 69−75. The abnormal expression of MMPs has been postulated to play a role in tumor invasion and metastasis.83 Almstead and colleagues84 developed compounds with a broad spectrum of MMP inhibitory activity by synthesizing derivatives of thiazine and thiazepine. They began by inserting a gem-dimethyl steric shielding group in the vicinity of a metal chelating hydroxamic acid functionality as a way to reduce metabolic inactivation of the pharmacophoric hydroxamic acid moiety (data not shown). Installation of a gem-dimethyl group in thiazine 69 and thiazepine 71 respectively produced 70 and 72, with a significant improvement in the in vitro inhibitory potency against all of the tested MMP isoforms (Figure 19). Since sulfides are prone to undergo oxidative metabolism (data not shown), the ring sulfur was oxidized to a sulfone derivative (as in 73) to improve metabolic stability, in vitro potency, and aqueous solubility compared to the sulfide analogues. Data indicated that the sulfone group was tolerated as evidenced from potent broad spectrum inhibition of all tested isoforms of MMPs, with an appreciable aqueous solubility of 0.8 mg/mL at 2179



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primary alcohol group in the form of a gem-dimethyl substitution, led to 81 (EC144),32 which had excellent potency and in vitro ADME profile (Figure 22). Moreover, 81 demonstrated an excellent in vivo oral PK profile in CD-1 mice (Cmax = 1556 ng/mL, Tmax = 0.5 h, AUC = 4419 ng·h/mL, and t1/2 = 1.5 h) and it was able to completely inhibit the growth of the N87 gastric tumors at a dose of 5 mg/kg (po, qd×5).32 Phosphoinositide 3-Kinase (PI3K) Inhibitor 85 (Taselisib). Aberrant PI3K signaling has been associated with certain cancers, and therefore, PI3K serves as a therapeutic target to develop anticancer drugs. Ndubaku and colleagues88 began PI3K inhibitor development program with a thiazolobenzoxepin-containing lead compound 82 (Figure 23); however, compound 82 had a very poor antitumor efficacy, which was attributed to its low water solubility and limited in vivo exposure to its unbound fraction. Consequently, these investigators optimized 82 to obtain new PI3K inhibitors with increased water solubility and minimal unbound clearance. These investigators recognized that a higher calculated distribution coefficient (clogD) led to more rapid clearance of unbound fraction. Therefore, it was envisioned that reducing clogD would lower the clearance of unbound fraction. This strategy resulted in replacement of the tricyclic lipophilic thiazolobenzoxepin ring (clogD = 2.7) system with the less lipophilic imidazolobenzoxazepin ring (clogD = 2.0), which resulted in 83, with marginal improvement in measured properties (Figure 23). Insertion of a gem-dimethyl group adjacent to the primary alcohol present in 83 led to 84 with improved potency and selectivity. Finally replacement of the hydroxyl group in R1 substituent with a primary carboxamide group resulted in clinical candidate 85 (GDC-0032/taselisib).88 The mouse PK profile of 84 and 85 was significantly improved compared to starting lead compound 82 (Figure 23). Retinoid X Receptor (RXR) Selective Activator Compound 88 (Bexarotene/Targretin). Compound 88 (LGD1069),89,90 is a highly selective RXR activator that is used to treat refractory or persistent early and refractory advanced stage cutaneous T-cell lymphoma. Since retinoids are essential to the modulation of proliferation and differentiation of normal and malignant cells, synthetic retinoids have the potential to treat dermatological diseases and cancer. On the basis of this premise, Boehm and colleagues89,90 developed retinoids possessing both high potency and larger selectivity for the RXR versus retinoic acid receptors (RARs). The EC50 values of compounds 86−88 indicated the loss of potency for compounds 86 (8-des-gem-dimethyl analogue) and 87 (5-desgem-dimethyl analogue) as compared to 88 (Figure 24). Increased potency and selectivity was realized when the gemdimethyl group was incorporated to the 5- and 8-positions of the tetrahydronaphthalene scaffold as in 88.89,90 Both the C5and C8-gem-dimethyl groups have favorable van der Waals interactions with helix H11 residues of the RXR receptor.91 Natural and Synthetic Retinoids. Compound 89 (tazarotene/tazorac) is a conformationally restricted, nonisomerizable member of the acetylenic class of topical retinoids for the treatment of acne and features the gem-dimethyl substituted thiocroman ring.92 The presence of alternate double bonds in 90 (tretinoin/retin-A) and 91 (isotretinoin/accutane) confers flexibility and receptor nonselectivity. This flexibility has been elegantly addressed by incorporating alternate double bonds within two (thiocroman and pyridine) ring structures and a linear acetylene bond (Figure 25).92 89 is an ethyl ester

prodrug that rapidly undergoes hydrolysis to release the pharmacologically active tazarotenic acid.92 89 regulates gene transcription by selectively binding to the nuclear receptors, RARβ and RARγ, which in turn leads to inhibition of terminal differentiation of keratinocytes and regulation of keratinocyte proliferation and apoptosis.93 Hence, it is topically used for the treatment of psoriasis. While 90 is an all-trans retinoic acid, 91 is a 13-cis retinoic acid (Figure 25). The gem-dimethyl group present in these retinoids formed favorable van der Waals interactions with helix H11 residues Cys432, His435, Leu436, and Phe439 of the retinoid receptor.91 Phosphoinositide 3-Kinase (PI3K) δ Specific Inhibitor 92. PI3Kδ is predominantly expressed in immune cells such as B cells where PI3Kδ is activated downstream of the B cell receptor.94 Since aberration in B cell signaling is essential to the pathophysiology of rheumatoid arthritis, targeting PI3Kδ could represent a strategy to develop drugs for the treatment of rheumatoid arthritis. Toward this end, Safina and colleagues95 developed potent, yet selective, inhibitors of PI3Kδ because nonselective inhibition of the α- and β-isoforms of PI3K causes embryonic lethality in knockout mice, and they are critical to insulin action and platelet aggregation. A potent and selective gem-dimethyl group-bearing PI3Kδ inhibitor, 92, was eventually identified using a structure-based drug design approach (Figure 26). The potency and selectivity of 92 were rationalized based on the structural analysis of the PI3Kδ active site (PDB code 2WXP).95 In the active site of PI3Kδ, Thr750, a smaller size residue, was observed above Trp760 in lieu of a larger size residue Arg as observed in PI3Kα and of a Lys in PI3Kβ and PI3Kγ isoforms. Consequently, PI3Kδ offers a vacant surface above Trp760, which is referred to as the tryptophan shelf. Insertion of a gem-dimethylpiperazine moiety, as in 92, was intended to exploit the tryptophan shelf to achieve a larger selectivity toward PI3Kδ over the other PI3K isoforms.95 Anticonvulsant Compound 93 (Topiramate/Topamax). Compound 93 was discovered through a standard in vivo screening test, the maximal electroshock seizure test.96 93 is derived from a monosaccharide that has an unusual C1sulfamate group (Figure 27). Replacement of a gem-dimethyl protected C4- and C5-ketal group with a spirocyclohexane ring or a complete removal of the gem-dimethyl group (thus generating free hydroxyl groups at the C4−C5) led to a complete loss of efficacy in the maximal electroshock seizure test. This result established the essential contribution of a gemdimethyl ketal functionality at C4−C5 in 93.96 Nicotinic Acetylcholine Receptor Antagonist (nAChR) 96. The antagonism of nAChR produces antidepressant effects in patients with major depressive disorders (MDD).97 The importance of the methyl groups in (±)-mecamylamine (94) is highlighted in Figure 28. The relative potencies of the pure (−)- and (+)-enantiomers in 94 (compounds 95 and 96, respectively) and of racemic 97 (lacking methyl at C2 and C3) are compared to racemic 94 (Figure 28).98 Compound 94 was able to antagonize the effect of nicotine in an assay for spontaneous activity and antinociception, with AD50 values of 0.24 mg/kg and 0.08 mg/kg, respectively. Compounds 94 and 95 were equipotent with respect to spontaneous depression activity.98 Conversely, 96 ((S)-(+)-mecamylamine/TC-5214/ targacept)99 did not produce any antagonism at 3 mg/kg.98 Both 95 and 96 were able to antagonize nicotine-induced nociception to a magnitude similar to that of 94. In contrast, 97, a C2- and C3-desmethyl analogue of 94, was inactive up to 10 mg/kg in both assays. SAR studies on these compounds 2180



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dimethyl moiety as evidenced from X-ray crystallographic studies.108 Potassium Ion Channel Opener 109 (Cromakalim). Potassium ion channel openers, by enhancing the efflux of potassium ions,109 have been shown to hyperpolarize the membrane potential of vascular smooth muscle cells.110 This action leads to vasodilation and a reduction in blood pressure.111 Consequently, Ashwood and co-workers112 developed benzopyran-3-ol derivatives as potent activators of the potassium ion channel. The importance of a gem-dimethyl substitution at the C2-position of the benzopyran scaffold is evident based on the successive increase in potency observed in analogues 106−108 (Figure 32). They hypothesized that the increased potency of 108 could be a result of the gem-dimethyl group’s contribution toward preventing its metabolic degradation (increased half-life). Since a C2-gem-dimethyl group was optimal, further SAR was focused on finding a replacement for the electron withdrawing nitro group, such as a cyano. These efforts led to discovery of the cyano substituted gem-dimethyl racemic analogue 109 (BRL34915/cromakalim)112 with improved potency. The chiral resolution of racemic 109 produced the corresponding levo- [(−)-110] and dextro[(+)-111] enantiomers and established the potency of 109 resided primarily with the levorotatory enantiomer (Figure 32).112 Liver X Receptor (LXR) Agonists 114 and 115. LXR agonists elicit an increase in reverse cholesterol transport and anti-inflammatory actions.113 One of the major concerns associated with LXR agonist development is the induction of targets implicated in lipogenesis, which eventually will also increase the production of VLDL in the liver and triglycerides in the liver and plasma.114 On the basis of this background, Kick and colleagues37 developed new compounds exhibiting a weak partial activity toward LXRα and enhanced activity toward LXRβ to achieve favorable reverse cholesterol transport and anti-inflammatory action, with concomitant reduction in lipogenesis. Early SAR studies led to identification of the pyrazole analogue, 112, with a 5-fold selectivity toward LXRβ over LXRα (Figure 33). Replacement of the trifluoromethyl group with the gem-dimethyl carbinol led to 113 and an 18-fold selectivity for LXRβ over LXRα. Since the gem-dimethyl carbinol-containing 113 exhibited high (4 h) plasma exposure and a 3-fold liver/plasma exposure ratio at 24 h, it was considered a favorable scaffold for the next round of SAR investigations. Compound 114, possessing an unsubstituted benzylic carbon that was appended to the C2-position of the imidazole core, showed impressive selectivity toward LXRβ. Insertion of a gem-dimethyl group into the benzylic carbon led to 115 and an improved PK profile (Figure 33).37 Sodium Hydrogen Exchanger 1 (NHE-1) Inhibitors 116 and 117. NHE-1, expressed predominantly in myocardial cells, is responsible for exchanging intracellular protons for extracellular sodium ions, a process that occurs during ischemia.115 Since selective inhibition of NHE-1 is an attractive strategy to treat myocardial ischemia and hypertension, Ahmad and co-workers48 developed potent and selective NHE-1 inhibitors bearing an acyl guanidine functionality. Optimized lead compound 116 showed submicromolar inhibition of hNHE-1. Insertion of a gem-dimethyl group in the cyclopropane ring of 116 led to 117 (BMS-284640),48 with a 13-fold improved inhibition of hNHE-1. This increase in potency by the gem-dimethyl group insertion could have resulted from (1) enhanced hydrophobic interactions with the NHE-1 binding

indicated the essential role of the C3-gem-dimethyl and C2methyl groups in nicotine antagonism.98 In 2010, (S)-(+)-96 entered into phase III clinical trial as an adjuvant treatment for MDD.99 5-Hydroxytryptamine 1A (5-HT1A) Receptor Agonist 98 (Gepirone/Travivo). Compound 98, a long-chain heteroaryl piperazine derivative, is structurally related to the anxiolytic drug buspirone (99/buspar, Figure 29). In March 2016, the U.S. FDA ruled favorably on the efficacy of 98 to treat MDD. Compound 98 was discovered in an effort to increase the affinity of 99 for the 5-HT1A receptor while minimizing its affinity for the D2 dopamine receptor. Replacement of a spirocyclopentane moiety at the C4-position of the piperidinedione scaffold in 99 with a gem-dimethyl group yielded 98, which had a higher affinity for the 5-HT1A receptor100 compared to the 5-HT2A receptor101 and D2 receptor.102 The binding affinity (Ki) of 99 for the 5-HT1A, 5-HT2A, and D2 receptors is shown in Figure 29.103 Human Renin Inhibitor 102 (Aliskiren/Tekturna). Blocking the interaction between renin and its substrate, angiotensinogen, is considered an attractive approach to treat hypertension.104 On the basis of prior work related to renin inhibitors,105 Maibaum and colleagues106 noted that the Nterminal carboxamide as P2′ groups had favorable in vitro and oral efficacy. Consequently, they modified the P2′ moiety in lead scaffold 100, with a carboxamide cap at the C-terminus. They obtained lead compound 100 and a high in vitro binding affinity for renin (Figure 30). To improve the in vitro and in vivo efficacy, further modifications were performed at the αcarbon of the carboxamide group. Insertion of a methyl group at the α-carboxamide position gave 101 (with either the (S) or (R) absolute configuration) with comparable binding affinity. Since both (S)- and (R)-stereochemistry at the α-carboxamide position produced similar binding affinity, it was predicted that insertion of a gem-dimethyl group would lead to a higher binding affinity and eliminate the chiral complexity associated with 101. This strategy led to the discovery of 102 (CGP060536B/SPP100/aliskiren),106 a subnanomolar renin inhibitor with good selectivity, excellent oral bioavailability, and a sustained duration of action. 102 was approved by the U.S. FDA to treat hypertension. An X-ray cocrystal structure of recombinant glycosylated human renin and 102 indicated a novel P2′ moiety in the S2′ pocket of the enzyme. In contrast to the earlier series with renin inhibitors containing an alkyl group as the P2′ moiety, the gem-dimethyl bearing P2′ moiety, as in 102, formed additional van der Waals interactions with the S2′ pocket of the enzyme, which could be responsible for the subnanomolar affinity of 102 toward renin.106 Hydroxymethyl Glutaryl Coenzyme A (HMG-CoA) Reductase Inhibitor 105 (Simvastatin/Zocor). Compound 105 is a semisynthetic statin and a close analogue of 103 (lovastatin/mevacor), a known inhibitor of HMG-CoA reductase, an essential enzyme that catalyzes the biosynthesis of cholesterol in mammalian cells. 105 was discovered by Hoffman and colleagues,107 starting from 103 (Figure 31). The α-methyl branching on the C1-butanoate moiety resulted in a new chiral center. Since both enantiomers (103 and 104) showed similar potency, the α-gem-dimethyl group was installed at the C1-butanoate to produce 105, with a >2-fold increase in potency. Moreover, the modification of 103 eliminated one chiral center and the ensuing complexity.107 The improved potency of 105 compared to 103 was attributed to a better filling of the hydrophobic pocket of the enzyme by a gem2181



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appears to be a viable strategy to develop new antiinflammatory drugs. Toward this end, Cai and co-workers123 developed a conformationally biased bicyclic MDP analogue such as 123 (Figure 37). Analogue 123 dose-dependently reduced TNF-α levels in macrophages exposed to P. gingivalis. Compared to MDP, 123 significantly reduced the severity of the endotoxic shock in mice produced by injection with P. gingivalis. Interestingly both in vitro and in vivo effects of 123 were superior to those produced by low and high doses of MDP. The contributory role of a gem-dimethyl moiety was evident from the lack of anti-inflammatory activity by 124, which was devoid of the gem-dimethyl ketal functionality (Figure 37).123 Interleukin-2 Inducible T-Cell Kinase (ITK) Inhibitor 128. ITK serves as a target to develop drugs for the treatment of inflammatory disorders such as asthma.124 Burch and colleagues125 developed potent and selective ITK inhibitors. They began discovery efforts with an optimized high throughput screening (HTS) hit compound that had problematic in vivo properties, such as poor aqueous solubility and suboptimal permeability, ascribed to a high aromatic ring count and a high topological polar surface area. Consequently, one of the aromatic rings (indazole) was partially saturated to the corresponding tetrahydroindazole ring, yielding lead compound 125 (Figure 38) to (a) enhance aqueous solubility, (b) exploit the out-of-plane hydrophobic interactions between the tetrahydroindazole ring and a lipophilic pocket comprising mostly aliphatic amino acids Val377, Ala389, and Lys391 and aromatic gatekeeper residue Phe435, and (c) increase selectivity because Phe435 is a rare aromatic amino acid to be present as a gatekeeper residue in kinases. Considering the proximity of aliphatic hydrophobic amino acids to C6 of the tetrahydroindazole ring, they installed a single methyl group at the C6position, thus obtaining 126 with comparable potency to 125 but no additional benefits. However, by inserting a gemdimethyl group at the C6-position, potency was increased by 6fold in 127 compared to 125. It may be noted that the cyano group in 125 was not beneficial. Conversely, the increased potency of 127 is a result of specific lipophilic interactions because moving the gem-dimethyl group from C6 to C5 resulted in a loss of potency. Further optimization of 127 was based on earlier observations126 indicating that a basic amino tail on a benzylic carbon tended to increase ITK potency, as well as aqueous solubility. These efforts culminated in 128 (GNE-9822)125 as a preclinical candidate. The positive impact of a C6-gem-dimethyl group to the efficacy of 128 was verified by solution of X-ray cocrystal structure (PDB code 4PQN) and analysis of compound 128 within the active site of ITK. Indeed, the C6-axial and the equatorial methyl groups produced lipophilic interactions with Phe435.125 Muscarinic M3 Receptor Antagonist 132. Activation of muscarinic receptor on airway smooth muscle cells has been linked to certain pulmonary diseases, such as asthma and COPD.127 Furthermore, antagonism of M 3 cholinergic receptors significantly decreases acetylcholine-induced airway smooth muscle contraction, an effect referred to as bronchodilation. The development of selective M3 receptor antagonists with a prolonged efficacy would be useful for the pharmacotherapy of asthma and COPD. To this end, Glossop and colleagues128 used an inhalation by design approach to discover muscarinic antagonists with long-acting action on the M3 receptor and reduced systemic absorption to curtail the incidence of adverse systemic effects. The screening of an in-

site and/or (2) steric bulk at the cyclopropane ring that sterically locked the free rotation about the aromatic ring and the acyl guanidine group.48 117 was also highly selective toward NHE-1 versus NHE-2, NHE-3, and NHE-5 (data not shown). In addition, 117 had an improved PK profile compared to 116 (Figure 34).48 Mammalian Target of Rapamycin (mTOR) Inhibitor 120. Dysregulation of mTOR is essential in the pathophysiology of metabolic disorders, cancer, and inflammation.116 Compounds 118 and 119, developed by Lynch and coworkers,117,118 had submicromolar affinity for mTOR, with a >100-fold selectivity over related lipid kinases. Subsequently, Cansfield and co-workers119 used a molecular hybrid design strategy of inserting the sulfone moiety of 118 into the fused pyrrolopyrimidine scaffold of 119 (Figure 35). These efforts led to a series of cyclic sulfones; however, interesting results were obtained when one of the benzylic carbons in the fivemembered cyclic sulfone was subjected to methylation. For instance, insertion of a gem-dimethyl substituent led to discovery of 120 (Z415) and showed a significant improvement in mTOR inhibition, selectivity, excellent cell-based potency, and an improved PK/PD profile.119 120 had a low molecular weight, high aqueous solubility, lack of CYP inhibition, low clearance, moderate plasma protein binding, acceptable oral bioavailability, and hERG inhibition with an IC50 of 48 μM.119 CC Chemokine Receptor 1 (CCR1) Antagonist 121. The antagonism of CCR1, a G-protein coupled receptor, in rodent models of inflammation suggests that its blockade is a viable strategy to develop anti-inflammatory drugs.120 Consequently, Santella and colleagues50 proceeded to develop a CCR1 antagonist possessing desirable properties such as (a) target affinity, (b) functional potency, (c) selectivity, (d) metabolic stability, (e) availability as a large free fraction in plasma, (f) favorable pharmacokinetics, (g) no PXR transactivation, and (h) no QT prolongation/cardiovascular effects. Ultimately, they synthesized 121 (BMS-817399),50 a clinical candidate, shown in Figure 36, that demonstrated potent inhibitory action against CCR1 and macrophage inflammatory protein (MIP)-1α-induced chemotaxis, along with a bioavailability of 79%, 46%, 100%, and 40%, respectively, in mouse, rat, dog, and monkey, 19% free fraction in serum, and no PXR activation up to 25 μM. Structurally, 121 features two gemdimethyl groups, each one playing a significant role in its therapeutic efficacy. First, the C3-gem-dimethyl substituent on the piperidine ring contributes toward the potency against both CCR1 and chemotaxis as evident from poor activity of the C3unsubstituted piperidine analogues prepared by the same group.121 Second, the gem-dimethyl of isopropanol moiety produces a steric clash with Phe288 in the PXR ligand-binding pocket to markedly lower the affinity of the gem-dimethyl carbinol-bearing CCR1 antagonists toward PXR. None of the low-energy conformers of 121 are in a position to escape this steric clash.50 Furthermore, with a single methyl adjacent to the hydroxyl group (as a secondary alcohol), the chiral analogues were metabolically unstable in liver microsomal preparations. This metabolic liability was addressed by the addition of a second methyl group, leading to a tertiary alcohol that was stable in microsomal preparations compared to the secondary alcohol analogues.50 Inhibitors of Porphyromonas gingivalis Induced Proinflammatory Effects (123). Since higher doses of muramyl dipeptide (MDP/compound 122) produced an antiinflammatory response,122 the synthesis of MDP analogues 2182



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house compound library to find M3 receptor antagonists with high affinity for and slow dissociation from the M3 receptor, led to identification of 129. It had a high binding affinity but an unacceptably rapid dissociation (half-life 38 min) for the M3 receptor (Figure 39). Interestingly, installation of a gemdimethyl group next to the basic tertiary amine moiety led to 130, with a significant improvement in M3 receptor binding affinity, as well as a slow rate of dissociation. It was rationalized that a gem-dimethyl substitution may have restricted the conformational freedom adjacent to the key basic amine pharmacophore. This conformational restriction may have induced a major reordering of 130 and the M3 receptor for a productive binding complex to occur, which in turn contributed to reduced rates of association and dissociation by 130.128 The slow dissociation of the ligand from the receptor was easily translated when the pyrrolidine ring of a chiral molecule 130 was replaced with a nonchiral azetidine ring (e.g., compound 131). Since inhaled anticholinergic drugs tend to produce adverse effects as a result of systemic exposure, these investigators focused their attention on optimizing the PK profile of 131. Toward this goal, a m-hydroxy group was added on the eastern phenyl ring, leading to discovery of the phase II clinical candidate 132 (PF-3635659).128 Compound 132 was suitable for once daily inhalation due to high affinity for the M3 receptor and a long dissociation half-life. In addition, 132 underwent rapid clearance by human liver microsomes and hepatocytes (Clint = 96 μL min−1 million−1) and was biotransformed to a significant extent by glucuronide conjugation (Clint = 221 μL min−1 mg−1), as shown in Figure 39.128 Phosphodiesterase 4 (PDE4) Type 4 Inhibitors 133 and 134. Since PDE4 is primarily expressed in proinflammatory immune and airway smooth muscle cells, it may serve as a therapeutic target to develop anti-inflammatory drugs for respiratory disorders.129 Selective inhibitors of PDE4A and -B are likely safer than nonselective inhibitors because the inhibition of PDE4D produces heart failure and arrhythmias.130 Taltavull and colleagues131 initiated the development of selective inhibitors of PDE4 based on a pyridothienopyrimidine lead scaffold. On the basis of PDE4 inhibitory activity profile for compounds 133 and 134, it became evident that insertion of a gem-dimethyl group onto a pyran ring was critical for the potency of this series (Figure 40). Compound 134 also showed appreciable inhibition of LPS-induced TNF-α production in the human whole blood (HWB) assay. Lysosomal Cysteine Protease (Cathepsin K) Inhibitor 136 (Odanacatib). Since cathepsin K is essential in proteolytic cleavage/degradation of collagen and other bone- and cartilageresident proteins, it serves as a therapeutic target for the development of osteoporosis drugs.132 Replacement of the two fluorine atoms in 135 with an isosteric methyl group led to fluoroisobutyl P2 moiety, as in 136 (MK-0822/odanacatib),133 with improved potency and selectivity toward cathepsin K versus other cysteine cathepsins (Figure 41). In addition, 136 also had an excellent PK profile in the rhesus monkey.133 To Enforce a Bioactive Conformation. Adenoviral Protease (AVP) Inhibitor 142. AVP is a cysteine protease adenain134 and is involved in several steps of the adenovirus life cycle.135 Since humans lack a corresponding adenain homolog, it represents a target to develop antiadenoviral drugs. Consequently, Grosche and co-workers136 used a crystalstructure-based and molecular-modeling-based approach to develop peptidomimetic/nonpeptidic scaffolds as useful, cell-

based, potent inhibitors of AVP. Compound 137, with an unsubstituted benzylic position, had weak AVP inhibitory activity (Figure 42). The substitution of one methyl group at the benzylic position gave 138, with ∼3-fold improvement in AVP inhibition. Insertion of a second methyl group at the benzylic position led to the AVP inhibitor, 139, whose potency was similar to that of prior peptidic analogues (IC50(AVP8) = 40 nM and IC50(AVP5) = 30 nM).136 It was hypothesized that the gem-dimethyl moiety forces 139 to adopt a preferred binding conformation within the active site of AVP. Although 139 had good cell permeability, it had an unacceptable aqueous solubility. Since molecular modeling studies suggested tolerance for larger groups in the methoxy binding pocket of AVP, the methoxy group was replaced with the water-solubilizing N,N-dimethylethoxy group, yielding 140, which manifested a slight enhancement in potency and a significantly higher aqueous solubility than 139. Both 139 and 140 had weak efficacy when tested using the antiviral cytopathic effect (CPE) assay (data not shown). Further SAR optimization was performed to depeptidize analogues 137−140 with the intention of obtaining cell-active compounds. Specifically, the cyanocarboxamide side chain was replaced with a surrogate cyanopyrimidine ring to obtain 141 and 142, with significant potency against AVP. Compound 142 possessed acceptable aqueous solubility and permeability and produced low micromolar efficacy in the CPE assay. These compounds did not significantly bind to plasma proteins and were >1700-fold more selective toward AVP8 over a panel of five human cysteine proteases (cathepsins).136 Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists 143 (Clofibrate/Atromid S), 144 (Fenofibrate/Triglide), and 145 (Gemfibrozil/Lopid). Fibrates are a class of lipid lowering drugs that activate PPARα.137 The mechanism of action of fibrates involves reduction in plasma lipid levels through induction of hepatomegaly and hepatic peroxisome proliferation in a PPARα-dependent manner. Consequently, fibrates may be of use for the treatment of obesity, cardiovascular diseases, and type 2 diabetes. An account of the evolution of fibrates, along with the role of the α-gem-dimethyl carboxylic acid pharmacophore, is briefly described here (Figure 43). Among several oxyisobutyric acid derivatives, compound 143 decreased total lipid and cholesterol concentrations in rat plasma and liver and had minimal toxicity.138 Although 143 was approved in 1967 by the U.S. FDA for the treatment of hyperlipidemias, it was later withdrawn due to hepatomegaly and concerns regarding hepatic peroxisome proliferation toxicity.139 To develop more potent antilipidemic drugs with minimum toxicity, 143 underwent further optimization. Specifically, two molecular modifications were performed: (1) replacing the pchloro group with a p-chlorobenzoyl group and (2) replacing the ethyl ester functionality with an isopropyl ester to provide 144, which was introduced to the U.S. market in late 1970s to treat hyperlipidemia.140 Compound 145, discovered in 1976, is another fibrate belonging to the phenoxy-α,α-dimethylpentanoic acid class.141 In a related phenoxyacetic acid series of fibrates (compounds 146 and 147), Sierra and colleagues142 reported that removal of the α-gem-dimethyl group (phenoxyisobutyric acid to phenoxyacetic acid) resulted in a 5- to 10-fold loss of affinity toward two PPAR subtypes (Figure 43). This effect was rationalized by Xray crystal structure studies on structurally related PPARα agonists, which suggested contribution of the α-gem-dimethyl 2183



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moiety in facilitating adoption of a conformation wherein the carboxylate and phenyl ring assumed a bioactive global minimum gauche relationship, as highlighted in Figure 43.143 Furthermore, a gem-dimethyl group was involved in favorable hydrophobic interactions within the receptor pocket formed by hydrophobic residues (Phe273, Val444, and Leu456) from helices 3, 7, 10, and 11 of PPAR.142,143 Glycoprotein IIb/IIIa (GPIIb/IIIa) Integrin Antagonist 148. Since binding of fibrinogen to the GPIIb/IIIa platelet surface receptor is the final common pathway for platelet aggregation through the cross-linking of platelets, development of GPIIb/IIIa antagonists is an attractive strategy to obtain antithrombotic drugs.144 Toward this goal, Hayashi and colleagues145 developed a potent and orally effective GPIIb/ IIIa antagonist prodrug 148 (racemate, Figure 44). The Cmax value in Figure 44 indicates a maximum concentration of active drug, i.e., an ethyl ester hydrolyzed to a carboxylic acid active metabolite. Compound 148 was found to achieve a bioactive cup-shaped and rigid conformation with the help of α-gemdimethyl and β-ethyl trisubstituted β-alanine central spacer.145 Enantiomerically pure (R)-148 was a highly potent platelet aggregation inhibitor with an IC50 of 22 nM, whereas (S)-148 had an IC50 of 3100 nM.145 Three-Dimensionality/Conformational Bias/Favorable Binding Entropy. A gem-dimethyl substituent can have two effects: (i) local conformational restriction to a bioactive conformation and (ii) van der Waals interactions within the target active site. A sterically restricted α-aminoisobutyric acid (Aib, Figure 45) is a natural, noncoded amino acid that is abundant in peptide antibiotics that exhibit antiviral and anticancer efficacies.146,147 Further Aib-containing peptides impose a decreased rotational freedom of the two peptide backbone angles φ and ψ compared to glycine or alanine.148 A gem-dimethyl substitution at the α-carbon is thoroughly documented to impart stable helical and β-turn conformations of the polypeptides.149,150 For example, Zuniga and colleagues151 designed, synthesized, tested, and determined the cocrystal structure of peptide-like inhibitors of botulinum neurotoxic serotype A light chain protease. Their design strategy incorporated a gem-dimethyl substitution at the glycine residue to enhance the 310 helical conformation and to decrease binding entropy. X-ray cocrystal structure data revealed the formation of van der Waals contacts between the side chain of Val70 and the gem-dimethyl group. This structure also showed a sharp turn at an adjacent residue that results from the steric constraint imposed by a gem-dimethyl moiety.151

Figure 46. Structures, in vitro potency, and PK profiles of antimalarial compounds 149−153.

Figure 47. Structures and in vitro potency of benzoxaboroles 154 and 155.

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Aib) yielded the highest potency compound, 150, which was comparable to 149. Two noticeable advantages of 150 over 149 and other compounds with a different amino acid component in the 7-side chain were lack of a chiral center and the presence of a metabolically stable gem-dimethyl substituted glycine side chain. Further SAR exploration was centered on the substitution pattern of the aniline ring at the 3-position of the imidazolopiperazine scaffold. These SAR experiments yielded the glycine and Aib derivatives 151 and 152, with potencies comparable to 149 and 150, respectively. The iv and oral PK properties in mice indicated a favorable profile for the gem-dimethyl glycine analogues, 150 and 152, compared to their glycine counterparts, 149 and 151. When subjected to biological testing, 150 and 152 proved highly efficacious in a rodent model of malaria, most likely due to their more favorable PK profiles. Furthermore, both 150 and 152 had an IC50 > 9 μM against drug metabolizing CYP450 isoforms and

CONTRIBUTION OF THE GEM-DIMETHYL GROUP TOWARD DRUG METABOLISM AND PHARMACOKINETICS (DMPK)/TOXICITY PROPERTIES Antimalarial Compound 153. Wu and colleagues152 synthesized a novel class of small molecules that was efficacious at inhibiting both wild-type and drug-resistant strains of the malarial strain P. falciparum. Subsequently, they optimized their cell-based HTS-derived imidazolopiperazine hit compound to obtain the glycine derivative 149. This compound inhibited both wild-type and drug-resistant P. falciparum at low nanomolar concentrations (Figure 46). Among the various examined amino acid side chains (i.e., alanine, valine, and phenylalanine) present at the 7-position of the imidazolopiperazine scaffold, the α-methylalanine (gem-dimethyl glycine/ 2184



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Figure 48. Structures, in vitro potency, and PK profiles of Wee1 kinase inhibitors 156−158.

Figure 49. Structures, in vitro potency, and DMPK profiles of LRRK2 inhibitors 159−163. aER: efflux ratio. bTDI: time-dependent inhibition.

had a CC50 > 12 μM against mammalian cell lines. Therefore, this class of compounds warranted further development. Metabolite experiments with 152 revealed the formation of a cyclized inactive metabolite, 152m, resulting from an intramolecular nucleophilic attack by Aib amine onto the sensitive benzylic C8 in the imidazolopiperazine ring. Consequently, Nagle and co-workers153 optimized 152 to improve the in vitro and in vivo potencies but also to obviate formation of the inactive cyclic metabolite, 152m. Consequently, insertion of a gem-dimethyl group at the benzylic C8 position led to a clinical candidate 153 (KAF156),153,154 which is presently undergoing phase II clinical trials. Benzoxaboroles as a Treatment for Stage 2 Human African Trypanosomiasis (HAT). HAT is a human disease caused by the single cell protozoan parasite Trypanosoma brucei brucei (T. b. brucei) spp.155 The first stage of the disease is characterized by the presence of trypanosomes in the

hemolymphatic system, whereas the second stage occurs when the parasite permeates through the blood−brain barrier, causing neurological dysfunction, disturbance of the sleep/wake cycle, and psychological changes.156 Due to limited treatment options for the second stage of HAT, there is an urgent medical need for new drugs to treat this human disease. The screening of approximately 50 benzoxaboroles in whole cell T. b. brucei led to disclosure of the first lead compound, 154 (SCYX6759),44 which had good efficacy against HAT stages 1 and 2; however, in the brain its concentration fell below the MIC within 15 h (Figure 47). Thus, to modulate the PK profile and particularly the CNS exposure of 154, the C3-position was subjected to substitution. Among the many C3-substitutions explored, the one that led to a desirable extended brain exposure occurred upon insertion of the C3-gem-dimethyl substituent as found in the clinical candidate, 155 (SCYX2185



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Figure 50. Structures, in vitro potency, and PK profiles of Cav2.2 inhibitors 164−170.

Figure 51. Structures, in vitro potency, and physicochemical profiles of mGlu2 receptor allosteric modulators 171−173. aPAM: positive allosteric modulator.

7158).45 In mice, 155 demonstrated brain exposure above the MIC for 24 h as compared to 15 h observed for 154.45 Wee1 Kinase Inhibitor 158. The negative regulation of Cdk1 by Wee1 kinase leads to repair of damaged DNA in the G2 phase prior to mitosis. Consequently, inhibitors of Wee1 kinase lead to premature mitosis of tumor cells, mitotic catastrophe, and ultimately to cell death.157 On the basis of this mechanism, Tong and co-workers46 started a Wee1 kinase inhibitor development program with a promising tricyclic core structure exemplified by compound 156 (Figure 48). Since 156 had excellent cellular activity, it was the subject of further SAR experiments that focused on structural modifications of the tetrahydroisoquinoline ring. Installation of a gem-dimethyl group at the C4-methylene of the tetrahydroisoquinoline ring resulted in 157, which had improved enzymatic activity and cellular efficacy.46 PK studies in mice clearly indicated a favorable contribution by the gem-dimethyl substituent toward

Figure 52. Structure, in vitro potency, and physicochemical and DMPK properties of FLAP inhibitor 174. ahWB: human whole blood. b RM: reactive metabolite.

Figure 53. Structure of LTD4 antagonist 175.

half-life, clearance, oral exposure, and bioavailability (Figure 48). After optimization of the gem-dimethyl substituted 2186



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moiety and its trifluoromethyl substituent were critical to binding to the active site of LRRK2, efforts were directed toward identifying a successful aniline surrogate. Early on, a 4aminopyrazole was identified as an efficient surrogate for the aniline moiety (compound 160), but with a cyanoethyl substituent it showed a high efflux ratio and a time-dependent inhibition (TDI) of the CYP1A2 isoform. On the basis of molecular modeling studies,159 it was evident that the pyrazoleN-capping group was located in a solvent-exposed region and could tolerate bulky substituents. As a result, a gem-dimethyl group was inserted adjacent to the cyano group of 160, leading to analogue 161, whose efficacy was comparable to that of 160 but with a slight reduction in human and rat liver microsomal clearance, significant reduction in efflux ratio, and no evidence of TDI of the CYP1A2.33 Replacement of the cyano group with a hydroxyl (compound 162) resulted in improved metabolic stability. Replacement of the C5-methyl group with an isosteric and isolipophilic chloro substituent led to 163, which had excellent cell-based potency (cell IC50 = 28 nM), excellent selectivity over 185 kinases, and aqueous solubility of 20 μg/ mL at physiological pH. The intraperitoneal administration of 10 mg/kg of 163 to mice produced significant concentrationdependent inhibition of phospho-LRRK2 levels in the brain.33 N-Type Calcium Channel (Cav2.2) Inhibitors 169 and 170. Dysfunction of the Cav2.2 channel in the spinal cord is involved in the development of chronic pain;160 thus it serves as a therapeutic target for the development of new drugs to treat pain. Shao and co-workers161 conducted experiments to improve the inhibitory activity of their previously reported aminopiperidine sulfonamide analogue, 164,162 that showed selective inhibitory activity for the Cav2.2 compared to the hERG and Cav1.2 channels. Although it demonstrated a dosedependent efficacy in preclinical models of hyperalgesia and neuropathic allodynia, it inhibited CYP3A4, activated PXR, and was metabolized to the circulating inactive sulfonamide metabolite, 165. An initial SAR exploration of the benzamide portion led to identification of 166, with greater potency than 164 and also an improved profile with respect to CYP3A4 inhibition and PXR activation (Figure 50). Further SAR, focused on modifying the hydrolytically unstable sulfonamide group, yielded a sulfone analogue 167 with a potency comparable to that of 164. Insertion of one methyl group at the α-position of the sulfone gave the chiral compound 168, with enantiospecific inhibition of the Cav2.2 channel. Removal of chirality by insertion of a gem-dimethyl group at the α-

Figure 54. Structures, in vitro potency, and physicochemical/PK profiles of S1P2 antagonists 176−179. nt: not tested.

Figure 55. Structure of PGE1 analogue 180.

tetrahydroisoquinoline ring, these investigators conducted SAR experiments that were directed toward the vacant second orthoposition of the chlorophenyl ring. Data indicated that the fluoro substituted analogue 158, compared to the chlorine substituted analogue, had significantly greater enzymatic and cellular efficacies and a better PK profile.46 Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor 163. Modulation of the kinase activity of LRRK2 could represent a therapeutic strategy to treat Parkinson’s disease.158 Consequently, Chan and colleagues33 synthesized a novel aminopyrazole class of LRRK2 inhibitors, starting from 159, a previously identified LRRK2 inhibitor (Figure 49).159 Compound 159 had moderate to poor aqueous solubility, the potential to generate a toxic and reactive o-quinoneimine metabolite and contained a metabolically unstable morpholinocarboxamide moiety. Therefore, efforts were directed at eliminating these liabilities by installation of a bioisosteric group in lieu of the aniline moiety. Since the aminopyrimidine

Figure 56. Structures, in vitro potency, and DMPK profiles of niacin receptor agonists 181−183. aAUCN: normalized area under the curve. 2187



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Figure 57. Structures, in vitro potency, and physicochemical/DMPK profiles of GK-GKRP disrupters 184−188. aTL: translocation.

importantly, 172 had an improved profile against the drug metabolizing enzyme CYP2C9 and a significantly reduced PXR activation compared to 171. To eliminate oxidative metabolic “hot spot” (a benzylic alcohol), these investigators incorporated a gem-dimethyl moiety, which led to 173 and improved potency and lower CYP2C9 liability. Compound 173 also demonstrated significant selectivity over the highly homologous mGlu3 receptor and other mGlu receptors, such as mGlu4, mGlu5, and mGlu6 (EC50 > 30 μM).38 5-Lipoxygenase Activating Protein (FLAP) Inhibitor 174. Interaction of 5-lipoxygenase (5-LO) with the FLAP protein facilitates the binding of arachidonic acid within the active site of 5-LO to stimulate production of inflammatory leukotrienes. Consequently, FLAP protein inhibitors have been developed for treating diseases characterized by inflammation, including asthma, because inhibition of the FLAP protein reduces the biosynthesis of inflammatory leukotrienes.164 Lemurell and co-workers164 developed a gem-dimethylcontaining compound 174 (AZD6642), shown in Figure 52, as a clinical candidate with excellent physicochemical and PK properties. The gem-dimethyl moiety adjacent to the hydroxyl group not only transformed the metabolically susceptible primary alcohol into a tert-alcohol but also sterically hindered potential phase 2 conjugation, as evidenced from rat and dog PK profile (Figure 52).164 Leukotriene D4 (LTD4) Antagonist 175. Compound 175 (montelukast/MK-476/singulair)165 is a gem-dimethyl carbinol substituted analogue approved by the U.S. FDA for the treatment of asthma and allergic rhinitis (Figure 53). Among various hydrogen bonding groups explored at the 2-position of the eastern phenyl ring, a tert-alcohol (gem-dimethyl carbinol) substitution provided a good balance of potent LTD 4 antagonism and rat plasma clearance.39 The ortho-gemdimethyl group seemed to play three roles: (i) blockade of benzylic carbon oxidation, (ii) prevention of alcohol oxidation, and (iii) making the alcohol group sterically hindered to prevent phase 2 glucuronide conjugation. Sphingosine 1-Phosphate 2 (S1P2) Antagonist 179. S1P2 antagonists are of particular interest since they could be used for the treatment of a broad range of disorders, including cancer166 and inflammation.167 Kusumi and colleagues42 began optimization at the aromatic carboxy-bearing phenoxy moiety

Figure 58. Structures and in vitro potency of 5-HT2C agonists 189 and 190.

position led to 169, with inhibitory action on Cav2.2 that was comparable to that of the most active enantiomer of 168. In addition, 169 provided significantly reduced PXR activation. Retention of the benzamide portion of 164 allowed for the synthesis of 170, which, however, showed a significantly reduced inhibitory power toward Cav2.2. In rats, 169 demonstrated a PK profile comparable to that of 164; however, it had a high efflux ratio by the human P-gp. Conversely, 170 showed a poor PK profile and elicited significant PXR activation, but its efflux ratio by the human P-gp was lower.162 Although 169 and 170 are far from becoming candidates for further development, they are devoid of metabolic conversion to an inactive sulfonamide metabolite and therefore can serve as interesting leads for further medicinal chemistry studies. Metabotropic Glutamate 2 (mGlu2) Receptor Allosteric Modulator 173. Selective activation of mGlu2 receptors could attenuate glutamatergic neurotransmission and, thus, serve as a viable approach to treat schizophrenia.163 Layton and colleagues38 conducted a study aimed at developing positive allosteric modulators of mGlu2 based on the HTS optimized lead compound 171. Compound 171 had an acceptable balance between pan mGlu2 potency and improved solubility at pH 7.0, compared to the original HTS-derived compound (Figure 51). Incorporation of a 2-methyl substituent on the phenyl ring led to the 2,5-disubstituted analogue, 172, with potency and aqueous solubility at pH 7.0 comparable to 171. More 2188



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Figure 61. Structures, in vitro potency, and hydrolytic stability of SGLT inhibitors 196−198.

Figure 62. Structures and pKa values of benzoxaboroles 199 and 200.

with reduced acidic character and moderate potency but desirable large values for AUC and Cmax parameters (Figure 54). An in vivo metabolic study with 176 indicated that this compound formed an acyl glucuronide as the major metabolite. Since acyl glucuronide conjugates of the phenyl acetic acid analogues are prone to produce idiosyncratic toxicity, it was hypothesized that steric crowding at the α-position of the acetic acid group in 176 would attenuate or obviate this concern.42 Subsequently, a monomethyl group was installed at the αposition of 176 to obtain 177, with a >2-fold increase in potency compared to 176. Further substitution at the αposition of 176 with a gem-dimethyl moiety led to 178, demonstrating >8-fold improvement in potency over 176. Investigation of the stability of the acyl glucuronide conjugates of 176 and 178 led authors to conclude that the acyl glucuronide conjugate of 178 was more stable than that of

Figure 59. Structures, in vitro potency, and DMPK profiles of antifungal compounds 191−195. aSGF: simulated gastric fluid. bSIF: simulated intestinal fluid.

of an early lead compound possessing significant acidic character (pKa of 3.85). Initially, this optimization program led to identification of a phenoxy acetic acid analogue, 176,

Figure 60. General structure of antibody drug conjugate. 2189



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This compound had a significant enhancement in disrupting potency, moderate to high nanomolar GKRP-binding affinity, and desirable in vitro PK properties. However, 185 failed to produce measurable activity in mouse hepatocytes, a result that was linked to its high lipophilicity and molecular weight. To overcome these drawbacks, a gem-dimethyl carbinol analogue 186 was designed to be less lipophilic and to have a lower molecular weight than 185. In addition, 186 had added advantage of containing one less chiral center. Although 186 showed disruption of the GK-GKRP complex comparable to 185, it also had excellent cell-based potency and a reduced efflux ratio, albeit with a slightly compromised clearance in rat liver microsomes. To increase biochemical and cellular potencies, these investigators implemented a structure-based drug design approach using the cocrystal structure of hGKRP and 186 (PDB code 4PXS). Specifically, they replaced the chlorophenyl ring with a 2-amino-5-chloropyrimidine ring (e.g., 187) and a 2-amino-5-chloro-3-fluoropyridine ring (e.g., 188) to increase overall efficacy and PK profile. Although both of these compounds demonstrated an excellent PK profile in the rat, 188 was more efficacious than 187 at lowering blood glucose in the db/db mouse model of obesity, diabetes, and dyslipidemia. The crystal structures of 186 (PDB code 4PXS) and 188 (PDB code 4PX5) bound to GKRP indicated the presence of an intermolecular hydrogen bond between the gemdimethyl carbinol moiety and gaunidinium side chain of Arg525.52 5-Hydroxytryptamine 2C (5-HT2C) Receptor Agonist 190. The 5-HT2C receptor serves as an important drug target for several CNS disorders such as obesity, schizophrenia, and drug addiction.173−175 The 5-HT2C receptor agonist 189, discovered by Bos and colleagues,176 has been shown to produce genotoxicity and DNA unwinding liabilities (Figure 58). Albertini and colleagues177 successfully mitigated these liabilities by insertion of a gem-dimethyl group at the methylene bridge of the tricyclic pyrazoloindene ring (compound 190), possibly due to a decrease in planarity induced by the gemdimethyl substitution.177 To Enhance Plasma Stability. Broad Spectrum Antifungal Compounds 194 and 195. Antifungal compounds with fungicidal activity are preferred over compounds with fungistatic activity. Toward this end, Bardiot and colleagues178 screened a compound library comprising ∼34 000 compounds. This led to the identification of novel 2-oxomorpholinoacetamide lead compound 191, which had significant fungicidal activity against Candida strains and fungistatic activity against Aspergillus strains (Figure 59). Since 191 contains a hydrolytically labile lactone functional group, these investigators performed a human plasma stability study of this compound, which indicated a very poor plasma stability (t1/2 = 22 min). To circumvent the poor plasma stability while retaining antifungal efficacy, the morpholine carbonyl group in 191 was replaced with a methylene, a change that decreased the potency of 191 by 4-fold. These data suggested the lactone moiety was critical for the antifungal activity of 191. Therefore, in the next structural modifications, steric bulk was incorporated into the C6 of the morpholin-2one ring with the notion that steric bulk next to the lactone would reduce susceptibility of the lactone ring to hydrolytic cleavage. Therefore, the sterically hindered monomethyl analogues 192 and 193 were prepared and found to possess antifungal efficacies similar to that of 191 but with a more than 2-fold increase in plasma stability. A further increase in steric

176. These data suggest that 178 is less likely to cause idiosyncratic toxicity as compared to 176. Since 178 had limited oral exposure, as evidenced from the poor AUC value, its western part was modified to improve oral absorption. Toward this goal, the piperidine ring was replaced with various saturated N-containing heterocyclic moieties. Among these a pyrrolidine ring (as found in compound 179) was shown to exhibit desirable potency and a significantly improved oral absorption and Cmax value (Figure 54).42 Prostaglandin E1 Analogue 180 (Gemeprost). Compound 180 (gemeprost/ONO 802) is a structural analogue of prostaglandin E1 that has abortifacient efficacy (Figure 55).168 Insertion of a gem-dimethyl group onto the C16-position of the prostaglandin scaffold resulted in longer-acting prostaglandins because a gem-dimethyl steric bulk prevented access of prostaglandin-15-hydroxy dehydrogenase to the allylic C15OH group present in 180.169 Niacin Receptor Agonist 183. It has been shown that niacin (nicotinic acid) decreases the hydrolysis of adipocyte triglycerides by binding to and activation of a high affinity nicotinic acid G-protein-coupled receptor (GPR109A).170 This mechanism leads to a reduction in plasma free fatty acid; however, niacin use is accompanied by side effects, including severe cutaneous flushing.171 Consequently, the development of new GPR109A agonists is an attractive strategy for the treatment of atherosclerosis without the side effects of niacin. Toward this goal, Shen and colleagues47 developed tetrahydroanthranilamide derivatives with high potency as GPR109A agonists with superior reduction of free fatty acids but significantly less cutaneous flushing than niacin. An SAR study was aimed at establishing whether the linker connecting the 1,2,4-oxadiazole with the anthranilamide moieties had a substantial impact on potency, serum shift, and PK properties. 181, an early stage lead compound, possessed reasonable binding affinity toward GPR109A and functional activity in the guanine nucleotide exchange (GTPγS) assay (Figure 56) but with a significant serum shift. This latter effect could be the result of 181 being a lipophilic weak acid. Insertion of a methyl group at the α-position of the linker led to identification of chiral compound 182 (enantiomer B), with a potency comparable to that of 181. Since the other enantiomer of 182 had a comparable binding affinity toward GPR109A, it was anticipated that a gem-dimethyl substitution at the α-position of the linker would produce a potency similar to that of 182.47 Indeed, the α-gem-dimethyl analogue 183 (MK-6892)47 had GPR109A binding affinity similar to that of 182, with even more improved half-life and reduced clearance values in the rat. Disrupters of Glucokinase−Glucokinase Regulatory Protein (GK-GKRP) Binding. Elevated levels of intracellular glucose have been shown to disrupt the inactive GK-GKRP complex (sequestered in the nucleus) and facilitate translocation of activated GK from the nucleus to the cytoplasm.172 Consequently, selective disrupters of the GK-GKRP complex may represent a novel strategy to treat type 2 diabetes. Pennington and co-workers52 developed a unique class of GKRP-selective disrupters of the GK-GKRP complex. 184 was an early analogue that had neither measurable disrupting ability on the hGK-hGKRP complex nor quantifiable activity in mouse hepatocytes (Figure 57). In addition, 184 was significantly metabolized by rat liver microsomes. To increase the potency and in vitro PK properties of 184, investigators inserted a carbinol-bearing aromatic/heteroaromatic ring at the C7position of the central benzothiophene scaffold to obtain 185. 2190



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STRUCTURAL ROLE OF A GEM-DIMETHYL GROUP To Induce Symmetry into a Chiral Center. Insertion of a gem-dimethyl group to induce symmetry at the chiral center is

bulk at the C6 of the morpholin-2-one ring in the form of a gem-dimethyl substitution (compound 194) also resulted in similar antifungal efficacy and an improved plasma stability (t1/2 > 240 min) relative to 191 (Figure 59). Since anilinecontaining compounds can occasionally induce toxicity, compound 194 was further optimized at the acetamide portion through replacement of the p-isopropylaniline moiety with a mbiphenylmethylamine, which led to the identification of 195. As with 194, compound 195 had good antifungal activity and an excellent plasma stability. The screening of compounds 194 and 195 against a panel of fungal strains suggested these compounds have broad-spectrum antifungal action.178 Antibody−Drug Conjugates (ADCs). ADC therapeutic strategy that involves selective targeting of tumor cells is a highly sought after field in the pharmaceutical industry. Anticancer ADC is comprised of a monoclonal antibody, suitable linker, and a cytotoxic drug (Figure 60). ADCs are also useful for treating nononcologic diseases.179 The steric hindrance of a gem-dimethyl substitution adjacent to the disulfide linker leads to increased disulfide bond stability, with ensuing slow reduction of the disulfide bond by glutathione in plasma when compared to the corresponding monomethyl substituted disulfide linkers.35 To Enhance Chemical Stability. Sodium-Dependent Glucose Cotransporters (SGLTs) Inhibitor 198. The SGLTs actively transport sugars across a cell membrane with concomitant sodium ion transport.180 This mechanism plays an important role in glycemic control. Consequently, SGLTs serve as therapeutic targets to develop antidiabetic drugs. Goodwin and colleagues34 focused on developing orally nonabsorbable selective SGLT1 inhibitors that can reside longer in the GI tract as a result of poor oral bioavailability. The SAR began with a xyloside-bearing scaffold in which structural modifications were conducted on substituents at the distal aryl ring. These efforts led to the N-methylpiperazine-containing lead compound, 196, with dual inhibition of SGLT1 and SGLT2; however, the carboxamide group was unstable to acid-catalyzed hydrolytic cleavage (Figure 61). To circumvent this problem, Gly was replaced with Aib to produce 197 with comparable inhibition profile but a greater hydrolytic stability. Finally an open chain analogue of a piperazine derivative, 197, led to identification of the dimethylaminoethyl analogue 198 (LX2761),34 which showed potent and similar inhibition of both SGLT1 and SGLT2 and was also stable to hydrolysis. 198 demonstrated excellent in vivo PK and efficacy profile in a C57 mouse model.34 Modulate the pKa of Nearby Functionality. Since introduction of the first boron-containing drug (velcade/ bortezomib) to the U.S. market, the use of boronic acids as pharmacophores has been actively pursued by medicinal chemists. Consequently, the need to fine-tune the physicochemical properties of these compounds, such as their acid strength, has become apparent. Tomsho and co-workers43 assessed the effect of varying the structure of the ring substituents to modulate the acid strength of the benzoxaboroles. For example, compound 199, lacking steric bulk at C3, had an aqueous pKa of 7.3, but insertion of a steric bulk in the form of a gem-dimethyl group at this position of the benzoxaborole ring produced 200, which had a one log unit higher pKa (i.e., decreased acid strength), as shown in Figure 62.43

Figure 63. Structures and in vitro potency of thrombin inhibitors 201−205. ab: bovine. bh: human.

Figure 64. Structures, in vitro potency, and physicochemical properties of GK activators 206−209.

evidenced in previously described examples. These include plasmepsin inhibitors (compounds 46 and 47), ICMT inhibitors (compounds 67 and 68), renin inhibitors (compounds 101 and 102), HMG-CoA reductase inhibitors (compounds 103 and 105), and Cav2.2 inhibitors (compounds 168 and 169). Other specific examples are described in the following section. Thrombin Inhibitors 201−205. Thrombin inhibitors are used for the treatment of venous and arterial thrombosis. Consequently, Brundish and colleagues181 initiated a thrombin inhibitor development program that relied upon the tetrahydroquinolinesulfonyl-Arg-piperidine peptidomimetic lead scaffold 201 (MD-805).182 Since the number of stereogenic centers in a molecule can hinder further chemical and clinical development efforts, these investigators attempted to develop more potent thrombin inhibitors along with a lower number of stereogenic 2191



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Figure 65. Structures and in vitro potency of DPP-IV inhibitors 210− 212.

centers compared to 201. Optimization of the P3 moiety led to identification of an achiral C3-unsubstituted derivative 202, with decreased potency compared to 201 (Figure 63). The racemic C3-methyl substituted P3 moiety-bearing analogue 203 was ∼10-fold more potent at inhibiting thrombin compared to 202. An enantiomerically pure C3-methyl P3 moiety, as in 204, was equipotent to the racemate 203. X-ray crystal structure studies have revealed the presence of an unoccupied space around the C3-position of the P3 moiety, an observation that prompted insertion of a second methyl group (that made C3 a nonstereogenic carbon), leading to compound 205, with a potency comparable to that of 204. Similarly, the two stereogenic centers present in the P2 moiety of lead scaffold 201 were removed by inserting a nonstereogenic hydroxyethylpiperidine P2 moiety. 205 produced dose-dependent inhibition of thrombus formation in both venous and arterial thrombosis animal models and proved better than 201 in an arterial thrombosis model.181 Glucokinase (GK) Activator 209. GK serves as a physiologic glucose sensor and is strictly regulated by plasma glucose levels.183 Consequently, GK could be a therapeutic target for the development of small molecule GK activators to treat diabetes. Dransfield and co-workers184 developed 4,5disubstituted-2-pyridyl ureas as GK activators. Extensive SAR studies around the 4- and 5-positions of the pyridine ring led to the identification of compound 206, with the desired potency

Figure 67. Structures, in vitro/in vivo potency, and physicochemical properties of β2-adrenoceptor agonists 216−218.

and a minimal shift in the presence of 4% human serum albumin (HSA), as shown in Figure 64. However, 206 exhibited poor PK properties in mice (F = 6%) and poor solubility (2000-fold selectivity over DPP8 and only weakly inhibited DPP-II.187 Negative Allosteric Modulators (NAM) of Metabotropic Glutamate Receptors 1 and 5 (mGlu1 and mGlu5). Since the mGlu1 and mGlu5 subtypes of the mGlu receptor are involved in many CNS disorders, they are of interest for the development of dual NAMs to treat CNS disorders. Toward this goal, Felts and co-workers188 initiated discovery chemistry work around a tricyclic pyridopyrazolopyrimidine-4-amine scaffold. They hypothesized that installation of the cycloalkyl substitutions at the 4-amino functionality of the tricyclic scaffold would exhibit improved druglike

Figure 69. Thorpe−Ingold conformational effect by a gem-dimethyl substituent at the noncyclic methylene group.

IC50 of 116 nM, a 31-fold selectivity over DPP8, and no inhibition of DPP-II (Figure 65). A subsequent branching at the α position of the glycine amine was investigated by insertion of a single methyl group to obtain 211, with a ∼2-fold improvement in DPP-IV inhibition compared to 210 and >99fold selectivity over DPP8. The promising effect resulting from a single methyl insertion prompted these investigators to increase steric bulk, as observed in a gem-dimethyl analogue

Figure 70. A three methyl lock o-hydroxydihydrocinnamic acid-derived promoiety and its influence on the rapid formation of δ-lactone with simultaneous release of paclitaxel. 2193



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Figure 71. Structures of microtubule assembly disrupter 228 and its bioreductive prodrugs 229 and 230.

Figure 72. Structures of some commercially available gem-dimethyl containing building blocks (231−268).

activity against mGlu5. On the basis of these results, they proceeded to insert a second methyl group at the 4-position of the cyclohexyl amine to generate the nonstereogenic C4-gemdimethylcyclohexyl amine analogue 215 (VU0467558).188 Compound 215 displayed significant NAM activity toward both mGlu1 and mGlu5 receptors. In addition, 215 also had a good DMPK profile (Figure 66). β2-Adrenoceptor Agonist 218. β2-Adrenoceptor agonists have been a mainstay in the pharmacotherapy of asthma and COPD. Glossop and co-workers189 developed an ultralongacting β2-adrenoceptor agonist suitable for use as a once-a-day inhalation treatment as well as a drug that had intrinsic crystallinity that would simplify solid state identification and candidate selection. The first analogue of this kind, 216, bearing a (R)-methyl group adjacent to the basic amine group, had excellent potency and selectivity; however, it was too polar, as evidenced from the clogP/log D value (Figure 67). It was observed that the (R)-methyl group formed key interactions with a β2-adrenoceptor to achieve potency and selectivity over the β1-adrenoceptor. Conversely, the (S)-methyl group was

Scheme 1. Examples of Base-Catalyzed Reactions for the gem-Dimethylation of the Benzylic Carbon

properties due to increased sp3-hybridized carbon count and also enhance potency. Subsequently, cyclohexyl analogue 213 was identified but manifested low affinity for both mGlu1 and mGlu5 receptors (Figure 66). A methyl substitution at the 4position of the cyclohexyl ring led to the trans-4-methylcyclohexyl amine derivative 214 and a significant increase in NAM activity against mGlu1 and a 13-fold increase in NAM 2194



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Scheme 2. Base-Catalyzed gem-Dimethylation of the KetoMethylene Functionality

Scheme 4. Examples of the gem-Dimethylcyclopropanation of Alkenes

neither positively nor negatively involved in ligand−receptor interactions. Thus, it was logical to install a gem-dimethyl group next to the basic amine, yielding 217, with retention of the potency and selectivity reported for 216; however, unlike 216, 217 had one less stereogenic center, thus making this compound simpler in terms of synthesis and future developmental work. These investigators hypothesized that an increase in lipophilicity would lead to an increase in duration of action. Moreover, they also intended to develop a drug with a lower incidence of adverse effects by the addition of “a phenolic handle” for glucuronide conjugation, to increase clearance following its systemic absorption via inhalation. To achieve these goals, they appended a phenol to the benzyl group and obtained 218 (PF-610355)189 with acceptable potency, selectivity, and more importantly, a 2-fold increase in duration of action. Furthermore, the solid form of 218 had properties that made it suitable for use as an inhalation powder dosage form.189 Anticancer Synthetic Analogues of Apratoxin A (219) and E (220). Apratoxins are cyanobacterial cyclodepsipeptides

with significant cytotoxicity against certain types of cancer cells.190 Hence, they can serve as a novel template for further SAR studies. Although 219 (Figure 68) demonstrated a broad range of antitumor efficacy,191 it also exhibited irreversible toxicity in vivo and was not well tolerated.192 Subsequently, Chen and co-workers193 linked the irreversible toxicity of 219 to the presence of a Michael acceptor group at C29, which was shown in vitro to form a covalent bond with glutathione. The only natural apratoxin that does not possess an α,β-unsaturated carbonyl group is 220; however, this compound suffers from poor cytotoxic efficacy, possibly due to lack of a C35-hydroxy group. Therefore, a new analogue, 221, which is a hybrid of 219 and 220, was designed and synthesized (Figure 68).193 Compound 221 contains the potency-enhancing C35-hydroxy group as in 219 but lacks the Michael acceptor toxicophore of 219, as in 220. Compound 222, a nonmethyl C34 derivative, was prepared to eliminate the chiral center, thus making the molecule simpler. Compound 223, a gem-dimethyl-C34 derivative, also removed the C34-chiral center, but the gemdimethyl group reduced the possibility of dehydration at C35 and subsequent formation of a double bond conjugated to the thiazoline ring system. All of the newly prepared apratoxin analogues, 221−223, demonstrated excellent antiproliferative efficacy against HCT116 cells (Figure 68). In addition, these compounds inhibited angiogenic vascular endothelial growth factor A (VEGF-A) at subnanomolar concentrations. Compound 223, though slightly less potent than 221 and 222, was

Scheme 3. Regioselective Opening of a Spirocyclopropane Ring To Produce gem-Dimethyl Derivatives

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Scheme 5. Addition of Methyl Anions to the Carbonyl Carbon of the Ester, Amide, and Ketone Groups

the central carbon move toward each other (compression of angle α from 112.2° to 109.5°) to facilitate ring closure, thereby forming a cyclized product.194 Subsequently, this strategy has been applied to design o-hydroxydihydrocinnamic acid based prodrugs as described in the following section. Application of the Thorpe−Ingold Conformational Effect in Prodrug Design. The three interacting methyl groups (highlighted red in Figure 70) present in an ohydroxydihydrocinnamic acid produce a conformational restriction that significantly increases the rate of cyclization (lactonization). Milstien and colleagues40 reported an increase in the kinetic and thermodynamic favorability of the lactonization of a three methyl locked o-hydroxydihydrocinnamic acid, 227, compared to derivatives 224−226. Consequently, a three methyl lock-bearing o-hydroxydihydrocinnamic acid was used to prepare prodrugs. The application of a three methyl lock in prodrug development is illustrated using paclitaxel (Figure 70). Paclitaxel (compound 7) has an extremely poor aqueous solubility, and as a result, it poses a concern for intravenous administration. To solve this problem, Ueda and colleagues41 prepared a water-soluble prodrug that was capable of releasing the active drug, i.e., paclitaxel, upon administration (Figure 70). A paclitaxel prodrug derived from the corresponding three methyl-lock-lacking promoiety is thought to undergo the first step, i.e., hydrolysis as expected; however, the cyclization (lactonization) step was too slow to efficiently release paclitaxel.195 gem-Dimethyl Substituted Bioreductive Prodrugs of Phenstatin (228). Development of bioreductive prodrugs of anticancer drugs is a useful strategy to target hypoxic tumors. Bioreductive prodrugs preferentially undergo reductive cleavage to release an active anticancer drug inside hypoxic tumors. Consequently, Winn and colleagues196 developed bioreductive

Scheme 6. Examples of Installation of the Carbinol Functionality via Nucleophilic Additions to Acetone

selected for in vivo studies because of its resistance to undergo inactivating C35-dehydration. Compound 223 produced a significant dose-dependent decrease in tumor growth in an HCT116 xenograft mouse model.193 Thorpe-Ingold Effect (gem-Dialkyl Effect). Beesley, Ingold, and Thorpe were the first investigators to notice a correlation between alterations in the bond angles of the carbon atoms of an open chain structure with the formation and stability of a cyclized product.194 Replacement of the methylene hydrogens with the sterically more demanding methyl group resulted in reduction of the internal bond angle α as shown in Figure 69. Consequently, the two reactive groups attached to 2196



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Table 1. Summary of the Contributions of the gem-Dimethyl Group toward the PK/PD/Physicochemical Properties of Selected Compounds Described in This Article

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Table 1. continued

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Table 1. continued

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Table 1. continued

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Table 1. continued

prodrugs of phenstatin (228), a disrupter of microtubule assembly, for selective targeting of hypoxic tumors. To this end, the 3-hydroxyl group of 228 was linked to the 5-nitrothiophene and 5-nitrofuran promoieties through a gem-dimethyl substituted methylene linker to produce 229 and 230, respectively (Figure 71). When 229 and 230 were subjected to CYP450 oxidoreductase enzyme, it was observed that both were completely cleaved to produce the parent drug 228 and a bystander promoiety.196 The gem-dimethyl-containing phenstatin prodrugs were more efficiently cleaved than their normethyl and monomethyl counterparts.196 Various Synthetic Approaches to Installation of the gem-Dimethyl Group. A large number of gem-dimethyl substituted building blocks (231−268) are commercially available for direct use in the synthesis of a wide range of bioactive compounds (Figure 72); however, these building blocks may not be suitable for certain drug discovery programs. Therefore, synthetic strategies for installation of the gemdimethyl group are critical for them to be useful to medicinal chemists. A brief account of major gem-dimethylation strategies is highlighted in this section and is no way intended to be exhaustive. Representative base-catalyzed reactions for the gem-dimethylation of a carbonyl-activated benzylic carbon are shown in Scheme 1. The gem-dimethylation of the aryl benzyl ketone (269) using potassium tert-butoxide and methyl iodide in THF furnished a gem-dimethyl substituted ketone (270).136 Similarly the treatment of the aryl acetate (271) with sodium hydride and methyl iodide in DMF yielded a gem-dimethyl substituted aryl acetate (272) as shown in Scheme 1.197 Gem-dimethylation of keto-methylene functionalities is depicted in Scheme 2. Regioselective gem-dimethylation of the cyclopentanone derivative (273) using an excess of methyl iodide and a slow addition of potassium tert-butoxide yielded a gem-dimethyl substituted cyclopentanone derivative (274).198 The gemdimethylation of bicyclic unsaturated ketone (275) occurred efficiently upon treatment with potassium tert-butoxide and methyl iodide to produce 276. Highly efficient gemdimethylation was observed when the tert-alcohol group was temporarily silylated using trimethylsilyl chloride, with subsequent removal by treatment with tetrabutylammonium fluoride.199 Ketone 277 was subjected to gem-dimethylation using sodium hydride and methyl iodide in dimethoxyethane to produce a gem-dimethyl derivative 278.200 Regioselective gemdimethylation of the enone 279 using potassium tert-butoxide and methyl iodide in tert-butanol led to the gem-dimethylated ketone 280 (Scheme 2).201

An alternative strategy employs regioselective opening of a spirocyclopropane ring (derived from exocyclic alkenes by following the modified Simmons−Smith reaction conditions), as in 281202 and 282,203 using hydrogen over platinum oxide, providing the gem-dimethyl derivatives 283 and 284 (Scheme 3). The gem-dimethyl cyclopropanation of the alkenes 285,204 286,48 and 287205 led, respectively, to the gem-dimethyl cyclopropane analogues 288, 289, and 290 (Scheme 4). Several examples of addition of two methyl anions to the carbonyl carbon of ester, amide, and ketone groups are depicted in Scheme 5. Treatment of the methyl ester 291 with the methyl Grignard reagent in THF led to a gem-dimethyl carbinol substituted derivative 292,37 while reaction with the monoester 293 in THF furnished the tert-alcohol 294.189 Similarly the ethyl ester 295 was treated with the methyl Grignard reagent to produce tert-alcohol 296.184 Treatment of the tert-amide 297 with either titanium tetrachloride or zirconium tetrachloride and subsequently with the methyl Grignard reagent produced a gem-dimethyl pyrrolidine derivative 298.128 Reaction of the acetyl substituted thiophene, 299, with either methyllithium in the presence of titanium tetrachloride or with trimethylaluminum yielded a gemdimethyl carbinol substituted thiophene derivative 300 (Scheme 5).196 Installation of a gem-dimethyl carbinol, a group frequently appearing in bioactive compounds, via nucleophilic additions to acetone is illustrated in Scheme 6. The quenching of the lithium anion of the benzylic carbon in 301 with acetone led to a gem-dimethyl carbinol 302.206 A lithium−iodine exchange of 2-chloro-4-iodopyridine (303) using n-butyllithium followed by reaction with acetone furnished a gem-dimethyl carbinol 304.52 Treatment of the purine derivative 305 with n-butyllithium followed by the addition of acetone yielded the C8-gemdimethyl carbinol 306 (Scheme 6).207 Some of the reactions described in Schemes 1−6 lack information on the percent yields of products because these products were used in the crude state for further chemical transformations.

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SUMMARY On the basis of the examples provided in this review, insertion of a natural-product-inspired gem-dimethyl moiety can be considered a useful structural feature in a wide range of lead optimization efforts. In this Perspective, numerous clinically useful compounds have been discussed (summarized in Table 1) to illustrate how a gem-dimethyl moiety can significantly contribute to favorable drug properties. For example, insertion of a gem-dimethyl group can (a) increase target engagement, potency, and selectivity, (b) induce symmetry at a monomethyl 2201



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Biography

substituted chiral center, (c) modulate the pKa of nearby acidic and basic functional groups, (d) delay or prevent phase 1 and phase 2 drug metabolism, (e) increase membrane permeability, chemical and plasma stability, oral bioavailability, AUC, CNS exposure, and t1/2, (f) decrease plasma clearance, CYP450 inhibition, PXR activation, P-gp efflux ratio, Ames genotoxicity, and hERG inhibition, (g) facilitate cyclative release of active drug from a three methyl lock prodrug, (h) accelerate release of cytotoxic drug from a bioreductive prodrug, and (i) decrease the reactivity of a glucuronide ester metabolite toward endogenous nucleophilic proteins and associated idiosyncratic toxicity. Furthermore, the gem-dimethyl moiety serves as an integral component of a myriad of natural products that have the potential for therapeutic use against a wide range of diseases. The gem-dimethylation of a 1,2-disubstituted bridged cyclopropane ring may be an effective way of increasing half-life and bioavailability while simultaneously reducing plasma clearance. Insertion of a gem-dimethyl group at the open chain methylene next to a labile functional group could potentially enhance chemical, plasma, and metabolic drug stability. While gemdimethyl substitution may be a useful way to mitigate timedependent inhibition of drug metabolizing CYP450 enzymes, the gem-dimethyl steric lobes could be exploited to achieve longer target residence time. Furthermore, it would be of interest to evaluate the impact of bioisosteric replacement of a gem-dimethyl group with the spirocyclopropane, spirocyclobutane, spirooxetane, and spiroazetidine moieties as determinants of PK/PD-related parameters. A successful drug is the result of combining a wide range of physicochemical and biological properties governing the drug’s PD/DMPK/toxicity profile, properties that could be addressed by the judicious use of a gem-dimethyl group. Although the number of U.S. FDA approved drugs containing a gem-dimethyl group is large, the exact role of a gem-dimethyl group in many of these examples is still not apparent. Therefore, studies aimed at understanding the role of a gem-dimethyl moiety in drug action will be needed using the additional gem-dimethyl/nongem-dimethyl matched molecular pairs. Moreover, the development of new synthetic strategies for installation of a gemdimethyl group will continue to enable gem-dimethyl group insertion into medicinally useful compounds. It is hoped that this Perspective will inspire medicinal chemists to use the gemdimethyl moiety in developing useful and effective preclinical and clinical drug candidates.

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Tanaji T. Talele obtained his Ph.D. (1998) in Medicinal Chemistry from the University of Mumbai, India. He was a postdoctoral fellow at UMD-New Jersey Medical School, Louisiana State University, and Moffitt Cancer Center (1999−2005). He joined the SJU’s College of Pharmacy and Health Sciences in 2005 where he is currently a Full Professor. He has authored/coauthored 88 peer-reviewed research papers. He has served as a reviewer for three grant agencies: Campbell Foundation FL, National Health and Medical Research Council (NHMRC) of the Government of Australia, and Fondazione Telethon, Italy. Since January 2016 he has been serving as an editorial advisory board member of the European Journal of Medicinal Chemistry. His current research interests include development of small molecule inhibitors of poly(ADP-ribose)polymerase and P-glycoprotein.

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ACKNOWLEDGMENTS The author is thankful to Drs. Charles R. Ashby, Jr., Cesar A. Lau-Cam, Uday Kiran Velagapudi (St. John’s University), Sanjai Kumar (Queens College, CUNY, NY), Mark McLaughlin (West Virginia University), and Vijay Gokhale (The University of Arizona) for their insights and critical review of the manuscript.

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ABBREVIATIONS USED AVP, adenoviral protease; Aib, α-aminoisobutyric acid; AR, androgen receptor; ADC, antibody−drug conjugate; AUC, area under the curve; CCR1, CC chemokine receptor 1; Cl, clearance; DHP-I, dehydropeptidase I; DPP-IV, dipeptidylpeptidase IV; GK, glucokinase; GK-GKRP, glucokinase−glucokinase regulatory protein; GPIIb/IIIa, glycoprotein IIb/IIIa; HSP90, heat shock protein 90; HAT, human African trypanosomiasis; hERG, human ether-a-go-go-related gene encoded potassium channel; HLM, human liver microsome; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; HWB, human whole blood; IGF-1R, insulin-like growth factor 1 receptor; ITK, interleukin-2 inducible T-cell kinase; ICMT, isoprenylcysteine carboxyl methyltransferase; LRRK2, leucine-rich repeat kinase 2; LTD4, leukotriene D4; FLAP, 5-lipoxygenase activating protein; LXR, liver X receptor; LHMDS, lithium hexamethyldisilazide; cathepsin K, lysosomal cysteine protease; mTOR, mammalian target of rapamycin; MMP, matrix metalloprotease; mGlu, metabotropic glutamate receptor; MIP, macrophage inflammatory protein; MLM, mouse liver microsome; MDP, muramyl dipeptide; MTH1, mutT homolog 1; NAM, negative allosteric modulator; nAChR, nicotinic acetylcholine receptor; PBP, penicillin binding protein; PPAR, peroxisome proliferator-activated receptor; P-gp, P-glycoprotein; PDE4, phosphodiesterase 4; PI3K, phosphoinositide 3kinase; Plm, plasmepsin; PSA, prostate specific antigen; PXR, pregnane X receptor; RLM, rat liver microsome; RSV, respiratory syncytial virus; RAR, retinoic acid receptor; RXR, retinoid X receptor; SIRT, silent information regulator; NHE, sodium hydrogen exchanger; S1P2, sphingosine 1-phosphate 2; TNFα, tumor necrosis factor α; VEGF-A, vascular endothelial growth factor A

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b00315. Molecular formula strings and associated biological data reported in this study (CSV)

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AUTHOR INFORMATION

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Corresponding Author

*Phone: (718) 990-5405. Fax: (718) 990-1877. E-mail: [email protected].

REFERENCES

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ORCID

Tanaji T. Talele: 0000-0002-5938-6505 Notes

The author declares no competing financial interest. 2202



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