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. Epub 2009 Dec 28.

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.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Biphenyl Compounds / administration & dosage*
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacokinetics*
  • Cathepsin K / antagonists & inhibitors*
  • Cathepsin K / metabolism
  • Cysteine Proteinase Inhibitors / administration & dosage*
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacokinetics*
  • Dogs
  • Drug Discovery / methods*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Macaca mulatta
  • Rabbits
  • Rats

Substances

  • Biphenyl Compounds
  • Cysteine Proteinase Inhibitors
  • MK 0674
  • Cathepsin K
  • odanacatib