Investigation of ketone warheads as alternatives to the nitrile for preparation of potent and selective cathepsin K inhibitors

Michael J Boyd; Sheldon N Crane; Joël Robichaud; John Scheigetz; W Cameron Black; Nathalie Chauret; Qingping Wang; Frédéric Massé; Renata M Oballa

doi:10.1016/j.bmcl.2008.12.053

Investigation of ketone warheads as alternatives to the nitrile for preparation of potent and selective cathepsin K inhibitors

Bioorg Med Chem Lett. 2009 Feb 1;19(3):675-9. doi: 10.1016/j.bmcl.2008.12.053. Epub 2008 Dec 24.

Authors

Michael J Boyd¹, Sheldon N Crane, Joël Robichaud, John Scheigetz, W Cameron Black, Nathalie Chauret, Qingping Wang, Frédéric Massé, Renata M Oballa

Affiliation

¹ Merck Frosst Centre for Therapeutic Research, Medicinal Chemistry, 16711 Trans Canada Hwy, PO Box 1005, Pointe-Claire-Dorval, Que., Canada H9R 4P8. [email protected]

PMID: 19117756
DOI: 10.1016/j.bmcl.2008.12.053

Abstract

Amino ketone warheads were explored as alternatives to the nitrile group of a potent and selective cathepsin K inhibitor. The resulting compounds were potent and selective inhibitors of cathepsin K and these nitrile replacements had a significant effect on metabolism and pharmacokinetics.

MeSH terms

Animals
Bile / metabolism
Biphenyl Compounds / chemical synthesis*
Biphenyl Compounds / chemistry
Cathepsin K / antagonists & inhibitors*
Cathepsin K / chemistry*
Chemistry, Pharmaceutical / methods*
Drug Design
Humans
Inhibitory Concentration 50
Ketones / analysis
Ketones / chemistry*
Models, Chemical
Nitriles / chemistry*
Osteoporosis / drug therapy
Rats
Structure-Activity Relationship
Time Factors

Substances

Biphenyl Compounds
Ketones
Nitriles
Cathepsin K
odanacatib