Discovery and ADMET: Where are we now

Current Topics in Medicinal Chemistry

Volumn 11, Issue 4, 2011, Pages 467-481

  Smith, Dennis A ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

Author keywords

Bile; Cyp450; Metabolites; Permeability; Physicochemistry; Screening; Transporters

Indexed keywords

CARVEDILOL; CIRAMADOL; DENOPAMINE; DOLASETRON MESILATE; DROLOXIFENE; ERLOTINIB; FENFLURAMINE; FLUTAMIDE; HALOGEN; LAPATINIB; LIGAND; LORATADINE; MORPHINE; PROPRANOLOL; SIBUTRAMINE; SUNITINIB; TRAMADOL; XAMOTEROL; ZOLMITRIPTAN;

ARTICLE; BILE FLOW; BILIARY EXCRETION; COMPUTER MODEL; DRUG ACTIVITY; DRUG DESIGN; DRUG METABOLISM; DRUG PENETRATION; DRUG SOLUBILITY; PHYSICAL CHEMISTRY; STRUCTURE ACTIVITY RELATION; URINARY EXCRETION;

ANIMALS; COMPUTER SIMULATION; DRUG DISCOVERY; HUMANS; PHARMACEUTICAL PREPARATIONS; PHARMACOKINETICS;

EID: 79551674594     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802611794480909     Document Type: Article

References (44)

1. Smith, D. A.; Jones, B. C.; Walker, D. K. Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics. Med. Res. Revs., 1996, 16(3), 243-266.
2. Lin, J.H. Role of pharmacokinetics in the discovery and development of indinavir. Adv. Drug Deliv. Rev., 1999, 39(1-3), 33-49.
3. Sugano, K.; Okazaki, A.; S. Shohei; Tavornvipas, S. Omura, A.; Mano, T. Solubility and dissolution profile assessment in drug discovery. Drug Metab. Pharmacokinet., 2007, 22(4), 225-254.
4. Volpe, D. A Variability in CaCo-2 and MDCK cell-based intestinal permeability assays. J. Pharm. Sci., 2008, 97(2), 712-725.
5. Austin, R.P.; Barton, P.; Cockcroft, S.L.; Wenlock, M.C.; Riley, R.J. The influence of nonspecific microsomal binding on apparent intrinsic clearance, and its prediction from physicochemical properties. Drug Metab. Dispos., 2002, 30(12), 1497-1503.
6. Parker, A. J.; Houston, J. B. Rate-limiting steps in hepatic drug clearance: comparison of hepatocellular uptake and metabolism with microsomal metabolism of saquinavir, nelfinavir, and ritonavir. Drug Metab. Dispos., 2008, 36(7), 1375-1384.
7. Rew, Y.; McMinn, D. L.; Wang, Z.; He, X.; Hungate, R. W.; Jaen, J. C.; Sudom, Athena; Sun, Daqing; Tu, Hua; Ursu, Stefania; Villemure, Elisia; Walker, Nigel P. C.; Yan, X.; Ye, Q.; Powers, J. P Discovery and optimization of piperidyl benzamide derivatives as a novel class of 11 β-HSD1 inhibitors. Bioorg. Med. Chem. Letts, 2009,19(6), 1797-1801.
8. Sandanayaka, V.; Mamat, B.; Mishra, R. K.; Winger, J.; Krohn, M.; Zhou, Li-M.; Keyvan, M.; Enache, L.; Sullins, D.; Onua, E.; Zhang, J.; Halldorsdottir, G.; Sigthorsdottir, H.; Thorlaksdottir, A.; Sigthorsson, G.T., Margret D.; Douglas R.; Stewart, L. J.; Zembower, D. E.; Andresson, T.; Kiselyov, A. S.; Singh, J.; Gurney, M. E. Discovery of 4-[(2S)-2-{[4-(4-Chlorophenoxy)phenoxy] methyl}-1-pyrrolidinyl]butanoic acid(DG-051) as a novel leukotriene A4 hydrolase inhibitor of leukotriene B4 biosynthesis. J. Med. Chem., 2009, 53(2), 573-585.
9. Ma, Q.; Lu, A. Y. The challenges of dealing with promiscuous drug-metabolizing enzymes, receptors and transporters. Curr. Drug Metab., 2008, 9(5), 374-383.
10. Thompson, T. N. Optimization of metabolic stability as a goal of modern drug design. Med. Res. Rev., 2001, 21(5), 412-449.
11. Skopalik, J.; Anzenbacher, P.; Otyepka, M. Flexibility of human cytochromes P 450: Molecular dynamics reveals differences between CYPs 3A4, 2C9, and 2A6, which correlate with their substrate preferences. J. Phys. Chem. B., 2008, 112(27), 8165-8173.
12. Ekroos, M.; Sjoegren, T. Structural basis for ligand promiscuity in cytochrome P 450 3A4. Procs. Nat. Acad. Sci, USA, 2006, 103(37), 13682-13687.
13. Trunzer, M.; Faller, B.; Zimmerlin, A. Metabolic soft spot identification and compound optimization in early discovery phases using MetaSite and LC-MS/MS validation. J. Med. Chem., 2009, 52, 329-335.
14. Burgey, C. S.; Robinson, K. A.; Lyle, T. A.; Sanderson, P. E. J.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Singh, R.; Miller-Stein, C.; White, R. B.; Wong, B.; Lyle, E. A.; Williams, P. D.; Coburn, C. A.; Dorsey, B. D.; Barrow, J. C.; Stranieri, M. T.; Holahan, M. A.; Sitko, G. R.; Cook, J. J.; McMasters, D. R.; McDonough, C. M.; Sanders, W. M.; Wallace, A. A.; Clayton, F. C.; Bohn, D.; Leonard, Y. M.; Detwiler, T. J., Jr.; Lynch, J. J., Jr.; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S. J.; Shafer, J. A.; Vacca, J. P. Metabolismdirected optimization of 3-aminopyrazinone acetamide thrombin inhibitors. development of an orally bioavailable series containing P1 and P3 pyridines. J. Med. Chem., 2003, 46(4), 461-473.
15. Marhefka, C. A.; Gao, W.; Chung, K.; Kim, J.; He, Y.; Yin, D.; Bo, C.; Dalton, J. T.; Miller, D. D. Design, synthesis, and biol. Characterization of metabolically stable selective androgen receptor modulators. J. Med. Chem., 2004, 47(4), 993-998.
16. Terasaka, T.; Tsuji, K.; Kato, T.; Nakanishi, I.; Kinoshita, T.; Kato, Y.; Kuno, M.; Inoue, T.; Tanaka, K.; Nakamura, K. Rational design of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors: Predicting enzyme conformational change and metabolism. J. Med. Chem., 2005, 48(15), 4750-4753.
17. Su, D-S.; Lim, J. L.; Tinney, E.; Wan, B-L.; Murphy, K. L.; Reiss, D. R.; Harrell, C. M.; O'Malley, S. S.; Ransom, R. W.; Chang, R. S. L.; Pettibone, D.J.; Yu, J.; Tang, C.; Prueksaritanont, T.; Freidinger, R. M.; Bock, M. G.; Anthony, N. J. 2-Aminobenzophenones as a novel class of bradykinin B1 receptor antagonists. J. Med. Chem., 2008, 51(13), 3946-3952.
18. 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(14), 4173-4191.
19. Fisher, M.B.; Kirk, R.H.; Boer, J. The complexities inherent in attempts to decrease drug clearance by blocking sites of CYPmediated metabolism. Curr. Opin. Drug Discov. Dev., 2006, 9(1), 101-109.
20. Ling, K; Kah, J.H.; Hanzlic, R.P. Deuterium isotope effects on toluene metabolism. Product release as a rate-limiting step in cytochrome P-450 catalysis. Bioch. Biophys. Res. Comms., 1989, 160(2), 844-849.
21. Atkinson, J.K.; Hollenberg, P.F.; Ingold, K.U.; Johnson, C.J., Le Tadic, M-H, Newcomb, M., Putt, D.A. Cytochrome P450-catalysed hydroxylation of hydrocarbons: kinetic deuterium isotope effects for the hydroxylation of an ultrafast radical clock. 1994, 33(35) 10630-10637.
22. Regal, K.A.; Kunze, K.L.; Peter, R.M.; Nelson, S.D. Oxidation of caffeine by CYP1A2: isotope effects and metabolic switching. Drug Metab. Dispos., 2005, 33(12) 1837-1844.
23. Smith D.A.; Obach R. S. Seeing through the MIST. Commentary on Metabolites in safety testing. Drug Metab. Dispos., 2005, 33(10), 1409-1417.
24. Smith, D. A.; Obach, R. S.; Williams, D. P.; Park, B. K. Clearing the MIST(metabolites in safety testing) of time: The impact of duration of administration on drug metabolite toxicity. Chem. Biol. Inter., 2009, 179(1), 60-67.
25. Smith, D. A.; Obach, R. S. metabolites in safety testing(mist): considerations of mechanisms of toxicity with dose, abundance, and duration of treatment. Chem. Res. Toxicol., 2009, 22(2), 267-279.
26. van Erp, N.P.; Gelderblom, H.; Guchelaar, H-J. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat. Rev., 2009, 35(8), 692-706.
27. Deeks, E.D.; Keating, G.M.; Sunitib. Drugs, 2006, 66(17) 2255-2266.
28. Cockerill, S.; Stubberfield, C.; Stables, J.; Carter, M.; Guntrip, S.; Smith, K.; McKeown, S.; Shaw, R.; Topley, P.; Thomsen, L.; Affleck, K.; Jowett, A.; Hayes, D.; Willson, M.; Woollard, P.; Spalding, D. Indazolylamino quinazolines and pyridopyrimidines as inhibitors of the EGFr and c-erbB-2. Bioorg. Med. Chem. Letts., 2001, 11(11), 1401-1405.
29. Hartz, R. A.; Ahuja, V. T.; Zhuo, X.; Mattson, R. J.; Denhart, D. J.; Deskus, J. A.; Vrudhula, V. M.; Pan, S.; Ditta, J. L.; Shu, Y.-Z.; Grace, J. E.; Lentz, K. A.; Lelas, S.; Li, Yu-Wen; Molski, T. F.; Krishnananthan, S.; Wong, H.; Qian-Cutrone, J.; Schartman, R.; Denton, R.; Lodge, N. J.; Zaczek, R.; Macor, J. E.; Bronson, J. J. A Strategy to Minimize Reactive Metabolite Formation: Discovery of(S)-4-(1-Cyclopropyl-2-methoxyethyl)-6-[6-(difluoromethoxy)- 2,5-dimethylpyridin-3-ylamino]-5-oxo-4,5-dihydropyrazine-2-carbonitrile as a potent, orally bioavailable corticotropin-releasing factor-1 receptor Antagonist. J. Med. Chem., 2009, 52(23), 7653-7668.
30. Kawai, M.; Sakurada, I.; Morita, Asato; Iwamuro, Yuko; Ando, Kazuo; Omura, Hirofumi; Sakakibara, Sachiko; Masuda, T.; Koike, H.; Honma, T.; Hattori, K.; Takashima, T.; Mizuno, K.; Mizutani, M.; Kawamura, M. Structure-activity relationship study of novel NR2B- selective antagonists with arylamides to avoid reactive metabolites formation. Bioorg. Med. Chem. Letts. 2007, 17(20), 5537-5542.
31. Aronov, A.M.; Mc Clain, B.; Moody, C. S.; Murcko, M. A. Kinaselikeness and kinase privileged fragements: towards virtual polypharmacology. J. Med. Chem., 2008, 51(5) 1214-1222.
32. Cox, C. D.; Breslin, Michael J.; Whitman, David B.; Coleman, Paul J.; Garbaccio, Robert M.; Fraley, Mark E.; Zrada, Matthew M.; Buser, Carolyn A.; Walsh, Eileen S.; Hamilton, Kelly; Lobell, Robert B.; Tao, Weikang; Abrams, Marc T.; South, Vicki J.; Huber, Hans E.; Kohl, Nancy E.; Hartman, George D. Kinesin spindle protein(KSP) inhibitors. Discovery of 2-propylamino-2,4- diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by β-fluorination to overcome cellular efflux by P-glycoprotein. Bioorg. Med. Chem. Letts., 2007, 17(10), 2697-2702.
33. Kato, Y.; Takahara, S.; Kato, S.; Kubo, Y.; Sai, Y.; Tamai, I.; Yabuuchi, H.; Tsuji, A. Involvement of multidrug resistanceassociated protein 2(Abcc2) in molecular weight-dependent biliary excretion of β-lactam antibiotics. Drug Metab. Dispos., 2008, 36(6), 1088-1096.
34. Uwai, Y.; Saito, H.; Inui, K. Rat renal organic anion transporter rOAT1 mediates transport of urinary-excreted cephalosporins, but not of biliary-excreted cefoperazone. Uwai, Yuichi; Saito, Hideyuki; Inui, Ken-ichi. Drug Met. Pharmacokinet, 2002, 17(2), 125-129.
35. Yang, X.; Ganhi, Y. A.; Duignan, D. B.; Morris, M. E. Predictive biliary excretion in rats and humans using molecular weight and quantitative structure-pharmacokinetic relationships. AAPS J., 2009, 11(3), 511-525.
36. Chen, Y.; Cameron, K.; Guzman-Perez, A.; Perry, D.; Li, D.; Gao, H. Structure-pharmacokinetic relationship of in vivo rat biliary excretion. Biopharm. Drug Dispos., 2010, 31(1), 82-90.
37. Gardner, I. B.; Walker, D. K.; Lennard, M. S.; Smith, D. A.; Tucker, G. T. Comparison of the disposition of two novel combined thromboxane synthase inhibitors/thromboxane A2 receptor antagonists in the isolated perfused rat liver. Xenobiotica, 1995, 25(2), 185-197.
38. Manner, C. N.; Payling, D. W.; Smith, D. A. Distribution coefficient, a convenient term for the relation of predictable physicochemical properties to metabolic processes. Xenobiotica, 1988, 18(3) 331-350.
39. Manner, C. N.; Payling, D. W.; Smith, D. A. Lipophilicity of zwitterionic sulphate conjugates of tiaramide, propranolol and 4'- hydroxypropranolol. Xenobitica, 1989, 19(12) 1387-1397.
40. Smith, D. A.; Brown, K.; Neale, M. G. Chromone-2-carboxlic acids: roles of acidity and lipophilicity in drug disposition. Drug Metab. Rev., 1985-1986, 16(4) 365-388.
41. Tang, W.; Stearns, R. A.; Chen, Q.; Bleasby, K.; Teffera, Y.; Colletti, A.; Hafey, M.; Evers, R.; Dean, D. C.; Magriotis, P. A.; Lanza, T. J.; Lin, L. S.; Hagmann, W. K.; Baillie, T. A. Importance of mechanistic drug metabolism studies in support of drug discovery: A case study with an N-sulfonylated dipeptide VLA-4 antagonist in rats. Xenobiotica, 2008, 38(2), 223-237.
42. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022128s002lbl.pdf
43. Grimm, S. W.; Einolf, H. J.; Hall, S. D.; He, K.; Lim, H.-K., Kah H. J.; Lu, C.; Nomeir, A. A.; Seibert, E.; Skordos, K. W.; Tonn, G. R.; Van Horn, R.; Wang, R. W.; Wong, Y. N.; Yang, T. J.; Obach, R. S. The conduct of in vitro studies to address time-dependent inhibition of drug -metabolizing enzymes: a perspective of the Pharmaceutical Research and Manufacturers of America. Drug Metabol. Dispos., 2009, 37(7), 1355-1370.
44. Quinney, S. K.; Zhang, X.; Lucksiri, A.; Gorski, J. C.; Li, L.; Hall, S. D. Physiologically based pharmacokinetic model of mechanismbased inhibition of CYP3A by clarithromycin. Drug Metab. Dispos., 2010, 38(2), 241-248.