1. The discovery of MK-0674, an orally bioavailable cathepsin K inhibitor.
- Author
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Isabel E, Bateman KP, Chauret N, Cromlish W, Desmarais S, Duong LT, Falgueyret JP, Gauthier JY, Lamontagne S, Lau CK, Léger S, LeRiche T, Lévesque JF, Li CS, Massé F, McKay DJ, Mellon C, Nicoll-Griffith DA, Oballa RM, Percival MD, Riendeau D, Robichaud J, Rodan GA, Rodan SB, Seto C, Thérien M, Truong VL, Wesolowski G, Young RN, Zamboni R, and Black WC
- Subjects
- Administration, Oral, Animals, Biological Availability, Biphenyl Compounds chemistry, Cathepsin K metabolism, Cysteine Proteinase Inhibitors chemistry, Dogs, Hepatocytes drug effects, Hepatocytes metabolism, Humans, Macaca mulatta, Rabbits, Rats, Biphenyl Compounds administration & dosage, Biphenyl Compounds pharmacokinetics, Cathepsin K antagonists & inhibitors, Cysteine Proteinase Inhibitors administration & dosage, Cysteine Proteinase Inhibitors pharmacokinetics, Drug Discovery methods
- Abstract
MK-0674 is a potent and selective cathepsin K inhibitor from the same structural class as odanacatib with a comparable inhibitory potency profile against Cat K. It is orally bioavailable and exhibits long half-life in pre-clinical species. In vivo studies using deuterated MK-0674 show stereoselective epimerization of the alcohol stereocenter via an oxidation/reduction cycle. From in vitro incubations, two metabolites could be identified: the hydroxyleucine and the glucuronide conjugate which were confirmed using authentic synthetic standards., (Copyright (c) 2009. Published by Elsevier Ltd.)
- Published
- 2010
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