The discovery of MK-0674, an orally bioavailable cathepsin K inhibitor

Autor:	W. Cameron Black, Jean-François Lévesque, Denis Riendeau, Jean-Pierre Falgueyret, Kevin P. Bateman, M. David Percival, Elise Isabel, Tammy LeRiche, Vouy Linh Truong, Jacques Yves Gauthier, Michel Therien, Robert Zamboni, Sevgi B. Rodan, Sylvie Desmarais, Christophe Mellon, Deborah A. Nicoll-Griffith, Renata Oballa, Gregg Wesolowski, Sonia Lamontagne, Carmai Seto, Nathalie Chauret, Chun Sing Li, Robert N. Young, Frédéric Massé, Wanda Cromlish, Daniel J. McKay, Le T. Duong, Cheuk K. Lau, Serge Leger, Joel Robichaud, Gideon A. Rodan
Rok vydání:	2010
Předmět:	Stereochemistry Cathepsin K Clinical Biochemistry Administration Oral Biological Availability Pharmaceutical Science Cysteine Proteinase Inhibitors Biochemistry Stereocenter chemistry.chemical_compound Dogs In vivo Drug Discovery Animals Humans Molecular Biology biology Biphenyl Compounds Organic Chemistry Macaca mulatta In vitro Rats chemistry Enzyme inhibitor Hepatocytes biology.protein Molecular Medicine Stereoselectivity Rabbits Glucuronide Odanacatib
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 20:887-892
ISSN:	0960-894X
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::04ce075aa9949065722c92768a34c9f4 https://doi.org/10.1016/j.bmcl.2009.12.083 Zobrazit plný text záznamu Full Text from ScienceDirect