Erratum: Mitigating heterocycle metabolism in drug discovery (Journal of Medicinal Chemistry (2012) 55 (6002-6020) DOI: 10.1021/jm300343m);Mitigating heterocycle metabolism in drug discovery

Journal of Medicinal Chemistry

Volumn 55, Issue 13, 2012, Pages 6002-6020

  St Jean, David J ^a   Fotsch, Christopher ^a  

^a AMGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,2,3 TRIAZOLE DERIVATIVE; 1,2,4 OXADIAZOLE DERIVATIVE; 1,2,4 TRIAZOLE DERIVATIVE; 1,3,4 OXADIAZOLE DERIVATIVE; 1,4 DIAZEPANE; 1,4 OXAZEPANE; AZEPANE; AZEPINE DERIVATIVE; AZETIDINE; FURAN; FURAZAN DERIVATIVE; IMIDAZOLE; ISOTHIAZOLE DERIVATIVE; ISOXAZOLE; MORPHOLINE; OXAZOLE; OXETANE; PIPERAZINE; PIPERIDINE; PYRAZOLE; PYRROLE; PYRROLIDINE DERIVATIVE; TETRAHYDROFURAN; TETRAHYDROPYRAN DERIVATIVE; TETRAZOLE DERIVATIVE; THIAZOLE; THIOPHENE; UNCLASSIFIED DRUG;

DRUG DEVELOPMENT; DRUG METABOLISM; DRUG STRUCTURE; REVIEW;

EID: 84863856481     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301579v     Document Type: Erratum

References (87)

1. Lin, J. H.; Lu, A. Y. H. Role of pharmacokinetics and metabolism in drug discovery and development Pharmacol. Rev. 1997, 49, 403-449 (Pubitemid 28030947)
2. Kumar, G. N.; Surapaneni, S. Role of drug metabolism in drug discovery and development Med. Res. Rev. 2001, 21, 397-411 (Pubitemid 32751462)
3. van de Waterbeemd, H.; Smith, D. A.; Beaumont, K.; Walker, D. K. Property-based design: optimization of drug absorption and pharmacokinetics J. Med. Chem. 2001, 44, 1313-1333 (Pubitemid 32852106)
4. Jang, G. R.; Harris, R. Z.; Lau, D. T. Pharmacokinetics and its role in small molecule drug discovery research Med. Res. Rev. 2001, 21, 382-396 (Pubitemid 32751461)
5. Thompson, T. N. Optimization of metabolic stability as a goal of modern drug design Med. Res. Rev. 2001, 21, 412-449 (Pubitemid 32751463)
6. Pritchard, J. F.; Jurima-Romet, M.; Reimer, M. L. J.; Mortimer, E.; Rolfe, B.; Cayen, M. N. A guide to drug discovery: making better drugs: decision gates in non-clinical drug development Nat. Rev. Drug Discovery 2003, 2, 542-553 (Pubitemid 37361746)
7. Shu, Y.-Z.; Johnson, B. M.; Yang, T. J. Role of biotransformation studies in minimizing metabolism-related liabilities in drug discovery AAPS J. 2008, 10, 178-192
8. Kola, I.; Landis, J. Opinion: Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discovery 2004, 3, 711-716
9. Meanwell, N. A. Synopsis of some recent tactical application of bioisosteres in drug design J. Med. Chem. 2011, 54, 2529-2591
10. Kerns, E. H.; Di, L. Drug-like Properties: Concepts, Structure, Design and Methods; Academic Press: San Diego, CA, 2008.
11. Smith, D. A. Discovery and ADMET: Where are we now? Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) 2011, 11, 467-481
12. Warr, W. ChEMBL. An interview with John Overington, team leader, chemogenomics at the European Bioinformatics Institute Outstation of the European Molecular Biology Laboratory (EMBL-EBI) J. Comput.-Aided Mol. Des. 2009, 23, 195-198
13. Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.; Obach, R. S.; ODonnell, J. P. Biotransformation reactions of five-membered aromatic heterocyclic rings Chem. Res. Toxicol. 2002, 15, 269-299 (Pubitemid 34241365)
14. Evans, D. C.; Watt, A. P.; Nicoll-Griffith, D. A.; Baillie, T. A. Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development Chem. Res. Toxicol. 2004, 17, 3-16 (Pubitemid 38134055)
15. Nassar, A.-E. F.; Kamel, A. M.; Clarimont, C. Improving the decision-making process in structural modification of drug candidates: reducing toxicity Drug Discovery Today 2004, 9, 1055-1064 (Pubitemid 39593655)
16. Kalgutkar, A. S.; Dalvie, D. K.; ODonnell, J. P.; Taylor, T. J.; Sahakian, D. C. On the diversity of oxidative bioactivation reactions on nitrogen-containing xenobiotics Curr. Drug Metab. 2002, 3, 379-424 (Pubitemid 34778004)
17. Kalgutkar, A. S.; Soglia, J. R. Minimising the potential for metabolic activation in drug discovery Expert Opin. Drug Metab. Toxicol. 2005, 1, 91-142
18. Kalgutkar, A. S.; Gardner, I.; Obach, R. S.; Shaffer, C. L.; Callegari, E.; Henne, K. R.; Mutlib, A. E.; Dalvie, D. K.; Lee, J. S.; Nakai, Y.; ODonnell, J. P.; Boer, J.; Harriman, S. P. A comprehensive listing of bioactivation pathways of organic functional groups Curr. Drug Metab. 2005, 6, 161-225 (Pubitemid 40753853)
19. Stepan, A. F.; Walker, D. P.; Bauman, J.; Price, D. A.; Baillie, T. A.; Kalgutkar, A. S.; Aleo, M. D. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States Chem. Res. Toxicol. 2011, 24, 1345-1410
20. Pryde, D. C.; Dalvie, D.; Hu, Q.; Jones, P.; Obach, R. S.; Tran, T.-D. Aldehyde oxidase: an enzyme of emerging importance in drug discovery J. Med. Chem. 2010, 53, 8441-8460
21. Argikar, U. A.; Mangold, J. B.; Harriman, S. P. Strategies and chemical design approaches to reduce the potential for formation of reactive metabolic species Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) 2011, 11, 419-449
22. Kumar, S.; Mitra, K.; Kassahun, K.; Baillie, T. A. Approaches for minimizing metabolic activation of new drug candidates in drug discovery Handb. Exp. Pharmacol. 2010, 196, 511-544
23. Parkinson, A.; Ogilvie, B. W. Biotransformation of Xenobiotics. In Casarett & Doulls Essentials of Toxicology, 2 nd ed.; Klaassen, C. D.; Watkins, J. B., III, Eds.; McGraw-Hill: New York, 2010.
24. Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications; Thieme Verlag: Stuttgart, Germany, 1996.
25. DAnna, F.; Frenna, V.; Pace, V.; Noto, R. Effect of ionic liquid organizing ability and amine structure on the rate and mechanism of base induced elimination of 1,1,1-tribromo-2,2-bis(phenyl-substituted)ethanes Tetrahedron 2006, 62, 1690-1698 (Pubitemid 43152071)
26. Pierson, P. D.; Fettes, A.; Freichel, C.; Gatti-McArthur, S.; Hertel, C.; Huwyler, J. r.; Mohr, P.; Nakagawa, T.; Nettekoven, M.; Plancher, J.-M.; Raab, S.; Richter, H.; Roche, O.; Rodríguez Sarmiento, R. M. a.; Schmitt, M.; Schuler, F.; Takahashi, T.; Taylor, S.; Ullmer, C.; Wiegand, R. 5-Hydroxyindole-2-carboxylic acid amides: novel histamine-3 receptor inverse agonists for the treatment of obesity J. Med. Chem. 2009, 52, 3855-3868
27. Adams, C. M.; Hu, C.-W.; Jeng, A. Y.; Karki, R.; Ksander, G.; LaSala, D.; Leung-Chu, J.; Liang, G.; Liu, Q.; Meredith, E.; Rao, C.; Rigel, D. F.; Shi, J.; Smith, S.; Springer, C.; Zhang, C. The discovery of potent inhibitors of aldosterone synthase that exhibit selectivity over 11-β-hydroxylase Bioorg. Med. Chem. Lett. 2010, 20, 4324-4327
28. Zbinden, K. G.; Anselm, L.; Banner, D. W.; Benz, J.; Blasco, F.; Décoret, G.; Himber, J.; Kuhn, B.; Panday, N.; Ricklin, F.; Risch, P.; Schlatter, D.; Stahl, M.; Thomi, S.; Unger, R.; Haap, W. Design of novel aminopyrrolidine factor Xa inhibitors from a screening hit Eur. J. Med. Chem. 2009, 44, 2787-2795
29. Dragovich, P. S.; Blazel, J. K.; Ellis, D. A.; Han, Q.; Kamran, R.; Kissinger, C. R.; LeBrun, L. A.; Li, L.-S.; Murphy, D. E.; Noble, M.; Patel, R. A.; Ruebsam, F.; Sergeeva, M. V.; Shah, A. M.; Showalter, R. E.; Tran, C. V.; Tsan, M.; Webber, S. E.; Kirkovsky, L.; Zhou, Y. Novel HCV NS5B polymerase inhibitors derived from 4-(1′,1′-dioxo-1′,4′-dihydro- 1′[lambda]6-benzo[1′,2′,4′]thiadiazin-3′-yl) -5-hydroxy-2 H -pyridazin-3-ones. Part 5: Exploration of pyridazinones containing 6-amino-substituents Bioorg. Med. Chem. Lett. 2008, 18, 5635-5639
30. Fish, P. V.; Brown, A. D.; Evrard, E.; Roberts, L. R. 7-Sulfonamido-3-benzazepines as potent and selective 5-HT2C receptor agonists: hit-to-lead optimization Bioorg. Med. Chem. Lett. 2009, 19, 1871-1875
31. Pescatore, G.; Kinzel, O.; Attenni, B.; Cecchetti, O.; Fiore, F.; Fonsi, M.; Rowley, M.; Schultz-Fademrecht, C.; Serafini, S.; Steinkühler, C.; Jones, P. Optimization of a series of potent and selective ketone histone deacetylase inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 5528-5532
32. Wan, Z.-K.; Chenail, E.; Xiang, J.; Li, H.-Q.; Ipek, M.; Bard, J.; Svenson, K.; Mansour, T. S.; Xu, X.; Tian, X.; Suri, V.; Hahm, S.; Xing, Y.; Johnson, C. E.; Li, X.; Qadri, A.; Panza, D.; Perreault, M.; Tobin, J. F.; Saiah, E. Efficacious 11β-hydroxysteroid dehydrogenase type I inhibitors in the diet-induced obesity mouse model J. Med. Chem. 2009, 52, 5449-5461
33. Kerekes, A. D.; Esposite, S. J.; Doll, R. J.; Tagat, J. R.; Yu, T.; Xiao, Y.; Zhang, Y.; Prelusky, D. B.; Tevar, S.; Gray, K.; Terracina, G. A.; Lee, S.; Jones, J.; Liu, M.; Basso, A. D.; Smith, E. B. Aurora kinase inhibitors based on the imidazo[1,2- a ]pyrazine core: fluorine and deuterium incorporation improve oral absorption and exposure J. Med. Chem. 2011, 54, 201-210
34. Melander, L.; Saunders, W. H., Jr. Reaction Rates of Isotopic Molecules; John Wiley and Sons: New York, 1979.
35. Shao, L.; Hewitt, M. C. The kinetic isotope effect in the search for deuterated drugs Drug News Perspect. 2010, 23, 398-404
36. Gleave, R. J.; Beswick, P. J.; Brown, A. J.; Giblin, G. M. P.; Goldsmith, P.; Haslam, C. P.; Mitchell, W. L.; Nicholson, N. H.; Page, L. W.; Patel, S.; Roomans, S.; Slingsby, B. P.; Swarbrick, M. E. Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB2 agonists for the treatment of inflammatory pain Bioorg. Med. Chem. Lett. 2010, 20, 465-468
37. Peglion, J.-L.; Goument, B.; Despaux, N.; Charlot, V.; Giraud, H.; Nisole, C.; Newman-Tancredi, A.; Dekeyne, A.; Bertrand, M.; Genissel, P.; Millan, M. J. Improvement in the selectivity and metabolic stability of the serotonin 5-HT1A ligand, S 15535: a series of cis- and trans-2- (arylcycloalkylamine) 1-indanols J. Med. Chem. 2002, 45, 165-176 (Pubitemid 34038552)
38. Qiao, L.; Choi, S.; Case, A.; Gainer, T. G.; Seyb, K.; Glicksman, M. A.; Lo, D. C.; Stein, R. L.; Cuny, G. D. Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors Bioorg. Med. Chem. Lett. 2009, 19, 6122-6126
39. Cramp, S.; Dyke, H. J.; Higgs, C.; Clark, D. E.; Gill, M.; Savy, P.; Jennings, N.; Price, S.; Lockey, P. M.; Norman, D.; Porres, S.; Wilson, F.; Jones, A.; Ramsden, N.; Mangano, R.; Leggate, D.; Andersson, M.; Hale, R. Identification and hit-to-lead exploration of a novel series of histamine H4 receptor inverse agonists Bioorg. Med. Chem. Lett. 2010, 20, 2516-2519
40. Omura, H.; Kawai, M.; Shima, A.; Iwata, Y.; Ito, F.; Masuda, T.; Ohta, A.; Makita, N.; Omoto, K.; Sugimoto, H.; Kikuchi, A.; Iwata, H.; Ando, K. The SAR studies of novel CB2 selective agonists, benzimidazolone derivatives Bioorg. Med. Chem. Lett. 2008, 18, 3310-3314 (Pubitemid 351718321)
41. Stepan, A. F.; Karki, K.; McDonald, W. S.; Dorff, P. H.; Dutra, J. K.; DiRico, K. J.; Won, A.; Subramanyam, C.; Efremov, I. V.; ODonnell, C. J.; Nolan, C. E.; Becker, S. L.; Pustilnik, L. R.; Sneed, B.; Sun, H.; Lu, Y.; Robshaw, A. E.; Riddell, D.; OSullivan, T. J.; Sibley, E.; Capetta, S.; Atchison, K.; Hallgren, A. J.; Miller, E.; Wood, A.; Obach, R. S. Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as gamma-secretase inhibitors J. Med. Chem. 2011, 54, 7772-7783
42. Lombardo, F.; Shalaeva, M. Y.; Tupper, K. A.; Gao, F. ElogDoct: A tool for lipophilicity determination in drug discovery. 2. Basic and neutral compounds J. Med. Chem. 2001, 44, 2490-2497 (Pubitemid 32852170)
43. Rotstein, D. M.; Gabriel, S. D.; Makra, F.; Filonova, L.; Gleason, S.; Brotherton-Pleiss, C.; Setti, L. Q.; Trejo-Martin, A.; Lee, E. K.; Sankuratri, S.; Ji, C.; deRosier, A.; Dioszegi, M.; Heilek, G.; Jekle, A.; Berry, P.; Weller, P.; Mau, C.-I. Spiropiperidine CCR5 antagonists Bioorg. Med. Chem. Lett. 2009, 19, 5401-5406
44. Pierson, P. D.; Freichel, C.; Gatti-MacArthur, S.; Hertel, C.; Huwyler, J.; Mohr, P.; Nakagawa, T.; Nettekoven, M.; Plancher, J.-M.; Raab, S.; Richter, H.; Roche, O.; Sarmiento, R. M. R.; Schmitt, M.; Schuler, F.; Takahashi, T.; Taylor, S.; Ullmer, C.; Wiegand, R. Histamine-3 receptor inverse agonists for the treatment of obesity: validation of the target and identification of novel series Chimia 2009, 63, 275-278
45. Zhang, X.; Tellew, J. E.; Luo, Z.; Moorjani, M.; Lin, E.; Lanier, M. C.; Chen, Y.; Williams, J. P.; Saunders, J.; Lechner, S. M.; Markison, S.; Joswig, T.; Petroski, R.; Piercey, J.; Kargo, W.; Malany, S.; Santos, M.; Gross, R. S.; Wen, J.; Jalali, K.; OBrien, Z.; Stotz, C. E.; Crespo, M. a. I.; Díaz, J.-L.; Slee, D. H. Lead Optimization of 4-acetylamino-2-(3,5-dimethylpyrazol-1- yl)-6-pyridylpyrimidines as A2A adenosine receptor antagonists for the treatment of Parkinsons disease J. Med. Chem. 2008, 51, 7099-7110
46. Ward, S. E.; Eddershaw, P.; Flynn, S. T.; Gordon, L.; Lovell, P. J.; Moore, S. H.; Scott, C. M.; Smith, P. W.; Thewlis, K. M.; Wyman, P. A. Studies on a series of potent, orally bioavailable, 5-HT1 receptor ligands-Part II Bioorg. Med. Chem. Lett. 2009, 19, 428-432
47. Fujimoto, T.; Imaeda, Y.; Konishi, N.; Hiroe, K.; Kawamura, M.; Textor, G. P.; Aertgeerts, K.; Kubo, K. Discovery of a tetrahydropyrimidin-2(1 H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor J. Med. Chem. 2010, 53, 3517-3531
48. Tsou, H.-R.; MacEwan, G.; Birnberg, G.; Grosu, G.; Bursavich, M. G.; Bard, J.; Brooijmans, N.; Toral-Barza, L.; Hollander, I.; Mansour, T. S.; Ayral-Kaloustian, S.; Yu, K. Discovery and optimization of 2-(4-substituted- pyrrolo[2,3- b ]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2 H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR) Bioorg. Med. Chem. Lett. 2010, 20, 2321-2325
49. Martignoni, M.; Kanter, R.; Moscone, A.; Grossi, P.; Monshouwer, M. Lack of strain-related differences in drug metabolism and efflux transporter characteristics between CD-1 and athymic nude mice Cancer Chemother. Pharmacol. 2005, 55, 129-135 (Pubitemid 40110055)
50. Mastalerz, H.; Chang, M.; Gavai, A.; Johnson, W.; Langley, D.; Lee, F. Y.; Marathe, P.; Mathur, A.; Oppenheimer, S.; Tarrant, J.; Tokarski, J. S.; Vite, G. D.; Vyas, D. M.; Wong, H.; Wong, T. W.; Zhang, H.; Zhang, G. Novel C-5 aminomethyl pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases Bioorg. Med. Chem. Lett. 2007, 17, 2828-2833 (Pubitemid 46656457)
51. Geng, B.; Basarab, G.; Comita-Prevoir, J.; Gowravaram, M.; Hill, P.; Kiely, A.; Loch, J.; MacPherson, L.; Morningstar, M.; Mullen, G.; Osimboni, E.; Satz, A.; Eyermann, C.; Lundqvist, T. Potent and selective inhibitors of Helicobacter pylori glutamate racemase (MurI): pyridodiazepine amines Bioorg. Med. Chem. Lett. 2009, 19, 930-936
52. Riether, D.; Wu, L.; Cirillo, P. F.; Berry, A.; Walker, E. R.; Ermann, M.; Noya-Marino, B.; Jenkins, J. E.; Albaugh, D.; Albrecht, C.; Fisher, M.; Gemkow, M. J.; Grbic, H.; Löbbe, S.; Möller, C.; OShea, K.; Sauer, A.; Shih, D.-T.; Thomson, D. S. 1,4-Diazepane compounds as potent and selective CB2 agonists: optimization of metabolic stability Bioorg. Med. Chem. Lett. 2011, 21, 2011-2016
53. Kalgutkar, A. S.; Driscoll, J.; Zhao, S. X.; Walker, G. S.; Shepard, R. M.; Soglia, J. R.; Atherton, J.; Yu, L.; Mutlib, A. E.; Munchhof, M. J.; Reiter, L. A.; Jones, C. S.; Doty, J. L.; Trevena, K. A.; Shaffer, C. L.; Ripp, S. L. A rational chemical intervention strategy to circumvent bioactivation liabilities associated with a nonpeptidyl thrombopoietin receptor agonist containing a 2-amino-4-arylthiazole motif Chem. Res. Toxicol. 2007, 20, 1954-1965
54. Obach, R. S.; Kalgutkar, A. S.; Ryder, T. F.; Walker, G. S. In vitro metabolism and covalent binding of enol-carboxamide derivatives and anti-inflammatory agents sudoxicam and meloxicam: insights into the hepatotoxicity of sudoxicam Chem. Res. Toxicol. 2008, 21, 1890-1899
55. Roth, S. H. Arthritis therapy: a better time, a better day Rheumatology (Oxford, U. K.) 2001, 40, 603-606 (Pubitemid 32621795)
56. Ahmed, M.; Khanna, D.; Furst, D. E. Meloxicam in rheumatoid arthritis Expert Opin. Drug Metab. Toxicol. 2005, 1, 739-751
57. Rostom, A.; Goldkind, L.; Laine, L. Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients Clin. Gastroenterol. Hepatol. 2005, 3, 489-498 (Pubitemid 40616915)
58. Ioannidis, S.; Lamb, M. L.; Almeida, L.; Guan, H.; Peng, B.; Bebernitz, G.; Bell, K.; Alimzhanov, M.; Zinda, M. Replacement of pyrazol-3-yl amine hinge binder with thiazol-2-yl amine: discovery of potent and selective JAK2 inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 1669-1673
59. Tremblay, M. R.; Lescarbeau, A.; Grogan, M. J.; Tan, E.; Lin, G.; Austad, B. C.; Yu, L.-C.; Behnke, M. L.; Nair, S. J.; Hagel, M.; White, K.; Conley, J.; Manna, J. D.; Alvarez-Diez, T. M.; Hoyt, J.; Woodward, C. N.; Sydor, J. R.; Pink, M.; MacDougall, J.; Campbell, M. J.; Cushing, J.; Ferguson, J.; Curtis, M. S.; McGovern, K.; Read, M. A.; Palombella, V. J.; Adams, J.; Castro, A. C. Discovery of a potent and orally active Hedgehog pathway antagonist (IPI-926) J. Med. Chem. 2009, 52, 4400-4418
60. For an example of metabolic ring-opening of an isoxazole ring see the following: Kalgutkar, A. S.; Nguyen, H. T.; Vaz, A. D. N.; Doan, A.; Dalvie, D. K.; McLeod, D. G.; Murray, J. C. In vitro metabolism studies of the isoxazole ring scission in the anti-inflammatory agent leflunomide to its active α-cyanoenol metabolite A771726: mechanistic similarities with cytochrome P450-catalyzed dehydration of aldoximes Drug Metab. Dispos. 2003, 31, 1240-1250 (Pubitemid 37152975)
61. For an example where the 1,2,5-oxadiazole ring was unchanged in a metabolism study see the following: Takegoshi, T.; Tachizawa, H.; Ohta, G. Steroids. XII. Metabolites of furazabol (17beta -hydroxy-17alpha-methyl-5alpha- androstano[2,3-c]furazan) administered to rats Chem. Pharm. Bull. 1972, 20, 1243-1259
62. Thomson, J. L.; Blackaby, W. P.; Jennings, A. S. R.; Goodacre, S. C.; Pike, A.; Thomas, S.; Brown, T. A.; Smith, A.; Pillai, G.; Street, L. J.; Lewis, R. T. Optimisation of a series of potent, selective and orally bioavailable GlyT1 inhibitors Bioorg. Med. Chem. Lett. 2009, 19, 2235-2239
63. Neitz, R. J.; Konradi, A. W.; Sham, H. L.; Zmolek, W.; Wong, K.; Qin, A.; Lorentzen, C.; Nakamura, D.; Quinn, K. P.; Sauer, J.-M.; Powell, K.; Ruslim, L.; Chereau, D.; Ren, Z.; Anderson, J.; Bard, F.; Yednock, T. A.; Griswold-Prenner, I. Highly selective c-Jun N-terminal kinase (JNK) 3 inhibitors with in vitro CNS-like pharmacokinetic properties II. Central core replacement Bioorg. Med. Chem. Lett. 2011, 21, 3726-3729
64. Barber, C. G.; Blakemore, D. C.; Chiva, J.-Y.; Eastwood, R. L.; Middleton, D. S.; Paradowski, K. A. 1-Amido-1-phenyl-3-piperidinylbutanes-CCR5 antagonists for the treatment of HIV. Part 1 Bioorg. Med. Chem. Lett. 2009, 19, 1075-1079
65. 14C]GSK977779 in rats and its implication with the observed covalent binding Drug Metab. Dispos. 2011, 39, 1620-1632
66. Metabolic ring opening of 2-amino-1,3,4-oxadiazole at the C-O bond has been observed: Maciolek, C. M.; Ma, B.; Menzel, K.; Laliberte, S.; Bateman, K.; Krolikowski, P.; Gibson, C. R. Novel cytochrome P450-mediated ring opening of the 1,3,4-oxadiazole in setileuton, a 5-lipoxygenase inhibitor Drug Metab. Dispos. 2011, 39, 763-770
67. Nordhoff, S.; Bulat, S.; Cerezo-Gálvez, S.; Hill, O.; Hoffmann-Enger, B.; López-Canet, M.; Rosenbaum, C.; Rummey, C.; Thiemann, M.; Matassa, V. G.; Edwards, P. J.; Feurer, A. The design of potent and selective inhibitors of DPP-4: optimization of ADME properties by amide replacements Bioorg. Med. Chem. Lett. 2009, 19, 6340-6345
68. Eastwood, P.; Esteve, C.; Gonzalez, J.; Fonquerna, S.; Aiguade, J.; Carranco, I.; Domenech, T.; Aparici, M.; Miralpeix, M.; Alberti, J.; Cordoba, M.; Fernandez, R.; Pont, M.; Godessart, N.; Prats, N.; Loza, M. I.; Cadavid, M. I.; Nueda, A.; Vidal, B. Discovery of LAS101057: a potent, selective, and orally efficacious A2B adenosine receptor antagonist ACS Med. Chem. Lett. 2011, 2, 213-218
69. Ishida, H.; Isami, S.; Matsumura, T.; Umehara, H.; Yamashita, Y.; Kajita, J.; Fuse, E.; Kiyoi, H.; Naoe, T.; Akinaga, S.; Shiotsu, Y.; Arai, H. Novel and orally active 5-(1,3,4-oxadiazol-2-yl)pyrimidine derivatives as selective FLT3 inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 5472-5477
70. Bailey, N.; Bamford, M. J.; Brissy, D.; Brookfield, J.; Demont, E.; Elliott, R.; Garton, N.; Farre-Gutierrez, I.; Hayhow, T.; Hutley, G.; Naylor, A.; Panchal, T. A.; Seow, H.-X.; Spalding, D.; Takle, A. K. Orally active C-6 heteroaryl- and heterocyclyl-substituted imidazo[1,2- a ]pyridine acid pump antagonists (APAs) Bioorg. Med. Chem. Lett. 2009, 19, 3602-3606
71. Gao, D. A.; Xiong, Z.; Heim-Riether, A.; Amodeo, L.; August, E. M.; Cao, X.; Ciccarelli, L.; Collins, B. K.; Harrington, K.; Haverty, K.; Hill-Drzewi, M.; Li, X.; Liang, S.; Margarit, S. M.; Moss, N.; Nagaraja, N.; Proudfoot, J.; Roman, R.; Schlyer, S.; Keenan, L. S.; Taylor, S.; Wellenzohn, B.; Wiedenmayer, D.; Li, J.; Farrow, N. A. SAR studies of non-zinc-chelating MMP-13 inhibitors: improving selectivity and metabolic stability Bioorg. Med. Chem. Lett. 2010, 20, 5039-5043
72. Morwick, T.; Büttner, F. H.; Cywin, C. L.; Dahmann, G.; Hickey, E.; Jakes, S.; Kaplita, P.; Kashem, M. A.; Kerr, S.; Kugler, S.; Mao, W.; Marshall, D.; Paw, Z.; Shih, C.-K.; Wu, F.; Young, E. Hit to lead account of the discovery of bisbenzamide and related ureidobenzamide inhibitors of Rho kinase J. Med. Chem. 2010, 53, 759-777
73. Ceccarelli, S. M.; Schlotterbeck, G.; Boissin, P.; Binder, M.; Buettelmann, B.; Hanlon, S.; Jaeschke, G.; Kolczewski, S.; Kupfer, E.; Peters, J.-U.; Porter, R. H. P.; Prinssen, E. P.; Rueher, M.; Ruf, I.; Spooren, W.; Stampfli, A.; Vieira, E. Metabolite identification via LC-SPE-NMR-MS of the in vitro biooxidation products of a lead mGlu5 allosteric antagonist and impact on the improvement of metabolic stability in the series ChemMedChem 2008, 3, 136-144
74. Kalgutkar, A. S.; Mascitti, V.; Sharma, R.; Walker, G. W.; Ryder, T.; McDonald, T. S.; Chen, Y.; Preville, C.; Basak, A.; McClure, K. F.; Kohrt, J. T.; Robinson, R. P.; Munchhof, M. J.; Cornelius, P. Intrinsic electrophilicity of a 4-substituted-5-cyano-6-(2-methylpyridin-3-yloxy)pyrimidine derivative: structural characterization of glutathione conjugates in vitro Chem. Res. Toxicol. 2011, 24, 269-278
75. McClure, K. F.; Darout, E.; Guimaraes, C. R. W.; DeNinno, M. P.; Mascitti, V.; Munchhof, M. J.; Robinson, R. P.; Kohrt, J.; Harris, A. R.; Moore, D. E.; Li, B.; Samp, L.; Lefker, B. A.; Futatsugi, K.; Kung, D.; Bonin, P. D.; Cornelius, P.; Wang, R.-D.; Salter, E.; Hornby, S.; Kalgutkar, A. S.; Chen, Y. Activation of the G-protein-coupled receptor 119: a conformation-based hypothesis for understanding agonist response J. Med. Chem. 2011, 54, 1948-1952
76. Hartz, R. A.; Ahuja, V. T.; Arvanitis, A. G.; Rafalski, M.; Yue, E. W.; Denhart, D. J.; Schmitz, W. D.; Ditta, J. L.; Deskus, J. A.; Brenner, A. B.; Hobbs, F. W.; Payne, J.; Lelas, S.; Li, Y.-W.; Molski, T. F.; Mattson, G. K.; Peng, Y.; Wong, H.; Grace, J. E.; Lentz, K. A.; Qian-Cutrone, J.; Zhuo, X.; Shu, Y.-Z.; Lodge, N. J.; Zaczek, R.; Combs, A. P.; Olson, R. E.; Bronson, J. J.; Mattson, R. J.; Macor, J. E. Synthesis, structure-activity relationships, and in vivo evaluation of N3-phenylpyrazinones as novel corticotropin-releasing factor-1 (CRF1) receptor antagonists J. Med. Chem. 2009, 52, 4173-4191
77. Zhuo, X.; Hartz, R. A.; Bronson, J. J.; Wong, H.; Ahuja, V. T.; Vrudhula, V. M.; Leet, J. E.; Huang, S.; Macor, J. E.; Shu, Y.-Z. Comparative biotransformation of pyrazinone-containing corticotropin-releasing factor receptor-1 antagonists: minimizing the reactive metabolite formation Drug Metab. Dispos. 2010, 38, 5-15
78. Hartz, R. A.; Ahuja, V. T.; Rafalski, M.; Schmitz, W. D.; Brenner, A. B.; Denhart, D. J.; Ditta, J. L.; Deskus, J. A.; Yue, E. W.; Arvanitis, A. G.; Lelas, S.; Li, Y.-W.; Molski, T. F.; Wong, H.; Grace, J. E.; Lentz, K. A.; Li, J.; Lodge, N. J.; Zaczek, R.; Combs, A. P.; Olson, R. E.; Mattson, R. J.; Bronson, J. J.; Macor, J. E. In vitro intrinsic clearance-based optimization of N3-phenylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists J. Med. Chem. 2009, 52, 4161-4172
79. Marriott, S.; Reynolds, W. F.; Taft, R. W.; Topsom, R. D. Substituent electronegativity parameters J. Org. Chem. 1984, 49, 959-965
80. Ceppi, E.; Eckhardt, W.; Grob, C. A. 4-Substituted quinuclidinium perchlorates in the determination of polar substituent effects Tetrahedron Lett. 1973, 3627-3630
81. Bannwart, L. M.; Carter, D. S.; Cai, H.-Y.; Choy, J. C.; Greenhouse, R.; Jaime-Figueroa, S.; Iyer, P. S.; Lin, C. J.; Lee, E. K.; Lucas, M. C.; Lynch, S. M.; Madera, A. M.; Moore, A.; Ozboya, K.; Raptova, L.; Roetz, R.; Schoenfeld, R. C.; Stein, K. A.; Steiner, S.; Villa, M.; Weikert, R. J.; Zhai, Y. Novel 3,3-disubstituted pyrrolidines as selective triple serotonin/norepinephrine/ dopamine reuptake inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 6062-6066
82. Wishka, D. G.; Walker, D. P.; Yates, K. M.; Reitz, S. C.; Jia, S.; Myers, J. K.; Olson, K. L.; Jacobsen, E. J.; Wolfe, M. L.; Groppi, V. E.; Hanchar, A. J.; Thornburgh, B. A.; Cortes-Burgos, L. A.; Wong, E. H. F.; Staton, B. A.; Raub, T. J.; Higdon, N. R.; Wall, T. M.; Hurst, R. S.; Walters, R. R.; Hoffmann, W. E.; Hajos, M.; Franklin, S.; Carey, G.; Gold, L. H.; Cook, K. K.; Sands, S. B.; Zhao, S. X.; Soglia, J. R.; Kalgutkar, A. S.; Arneric, S. P.; Rogers, B. N. Discovery of N -[(3 R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3- c ]pyridine-5-carboxamide, an agonist of the alpha 7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure-activity relationship J. Med. Chem. 2006, 49, 4425-4436 (Pubitemid 44036685)
83. Linton, A.; Kang, P.; Ornelas, M.; Kephart, S.; Hu, Q.; Pairish, M.; Jiang, Y.; Guo, C. Systematic structure modifications of imidazo[1,2- a ]pyrimidine to reduce metabolism mediated by aldehyde oxidase (AO) J. Med. Chem. 2011, 54, 7705-7712
84. Garattini, E.; Mendel, R.; Romao, M. J.; Wright, R.; Terao, M. Mammalian molybdo-flavoenzymes, an expanding family of proteins: structure, genetics, regulation, function and pathophysiology Biochem. J. 2003, 372, 15-32 (Pubitemid 36609603)
85. Torres, R. A.; Korzekwa, K. R.; McMasters, D. R.; Fandozzi, C. M.; Jones, J. P. Use of density functional calculations to predict the regioselectivity of drugs and molecules metabolized by aldehyde oxidase J. Med. Chem. 2007, 50, 4642-4647 (Pubitemid 47463238)
86. Lunniss, C.; Eldred, C.; Aston, N.; Craven, A.; Gohil, K.; Judkins, B.; Keeling, S.; Ranshaw, L.; Robinson, E.; Shipley, T.; Trivedi, N. Addressing species specific metabolism and solubility issues in a quinoline series of oral PDE4 inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 137-140
87. Boström, J.; Hogner, A.; Llinàs, A.; Wellner, E.; Plowright, A. T. Oxadiazoles in medicinal chemistry J. Med. Chem. 2012, 55, 1817-1830