A structural screening approach to ketoamide-based inhibitors of cathepsin K

David G Barrett; John G Catalano; David N Deaton; Stacey T Long; Robert B McFadyen; Aaron B Miller; Larry R Miller; Kevin J Wells-Knecht; Lois L Wright

doi:10.1016/j.bmcl.2005.03.023

A structural screening approach to ketoamide-based inhibitors of cathepsin K

Bioorg Med Chem Lett. 2005 May 2;15(9):2209-13. doi: 10.1016/j.bmcl.2005.03.023.

Authors

David G Barrett¹, John G Catalano, David N Deaton, Stacey T Long, Robert B McFadyen, Aaron B Miller, Larry R Miller, Kevin J Wells-Knecht, Lois L Wright

Affiliation

¹ Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.

PMID: 15837295
DOI: 10.1016/j.bmcl.2005.03.023

Abstract

Several novel ketoamide-based inhibitors of cathepsin K have been identified. Starting from a modestly potent inhibitor, structural screening of P2 elements led to 100-fold enhancements in inhibitory activity. Modifications to one of these leads resulted in an orally bioavailable cathepsin K inhibitor.

MeSH terms

Amides / chemical synthesis
Amides / pharmacokinetics
Amides / pharmacology*
Binding Sites
Biological Availability
Cathepsin K
Cathepsins / antagonists & inhibitors*
Cathepsins / chemistry
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology*
Humans
Kinetics
Protein Conformation
Recombinant Proteins / antagonists & inhibitors
Recombinant Proteins / chemistry
Structure-Activity Relationship

Substances

Amides
Enzyme Inhibitors
Recombinant Proteins
Cathepsins
CTSK protein, human
Cathepsin K