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

  • Bioorg Med Chem Lett. 2010 Feb 1;20(3):887-92. doi: 10.1016/j.bmcl.2009.12.083.
Elise Isabel  1 ,  Kevin P Bateman ,  Nathalie Chauret ,  Wanda Cromlish ,  Sylvie Desmarais ,  Le T Duong ,  Jean-Pierre Falgueyret ,  Jacques Yves Gauthier ,  Sonia Lamontagne ,  Cheuk K Lau ,  Serge Léger ,  Tammy LeRiche ,  Jean-François Lévesque ,  Chun Sing Li ,  Frédéric Massé ,  Daniel J McKay ,  Christophe Mellon ,  Deborah A Nicoll-Griffith ,  Renata M Oballa ,  M David Percival ,  Denis Riendeau ,  Joël Robichaud ,  Gideon A Rodan ,  Sevgi B Rodan ,  Carmai Seto ,  Michel Thérien ,  Vouy Linh Truong ,  Gregg Wesolowski ,  Robert N Young ,  Robert Zamboni ,  W Cameron Black
Affiliations
  • 1. Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Québec, Canada H9H 3L1. [email protected]
PMID: 20061146 DOI: 10.1016/j.bmcl.2009.12.083
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.

Products