Novel route to the synthesis of peptides containing 2-amino-1'-hydroxymethyl ketones and their application as cathepsin K inhibitors

Rohan V Mendonca; Shankar Venkatraman; James T Palmer

doi:10.1016/s0960-894x(02)00611-x

Novel route to the synthesis of peptides containing 2-amino-1'-hydroxymethyl ketones and their application as cathepsin K inhibitors

Bioorg Med Chem Lett. 2002 Oct 21;12(20):2887-91. doi: 10.1016/s0960-894x(02)00611-x.

Authors

Rohan V Mendonca¹, Shankar Venkatraman, James T Palmer

Affiliation

¹ Celera, 180 Kimball Way, South San Francisco, CA 94080, USA. [email protected]

PMID: 12270170
DOI: 10.1016/s0960-894x(02)00611-x

Abstract

Cathepsin K is highly expressed in human osteoclasts, and is implicated in bone resorption. This makes it an attractive target for the treatment of osteoporosis. Peptides containing 2-amino-1'-hydroxymethyl ketones and 2-amino-1'-alkoxymethyl ketones were discovered as potent inhibitors of cathepsin K. A novel synthetic route was devised to facilitate rapid elucidation of the SAR of these inhibitors. The synthesis and SAR of hydroxymethyl ketones are presented.

MeSH terms

Cathepsin K
Cathepsins / antagonists & inhibitors*
Drug Design
Humans
Indicators and Reagents
Ketones / chemical synthesis*
Ketones / pharmacology*
Osteoclasts / drug effects
Osteoclasts / enzymology
Osteoporosis / drug therapy
Peptides / chemical synthesis*
Peptides / pharmacology*
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / pharmacology*
Stereoisomerism
Structure-Activity Relationship

Substances

Indicators and Reagents
Ketones
Peptides
Protease Inhibitors
Cathepsins
CTSK protein, human
Cathepsin K