Acyclic, orally bioavailable ketone-based cathepsin K inhibitors

David G Barrett; John G Catalano; David N Deaton; Stacey T Long; Robert B McFadyen; Aaron B Miller; Larry R Miller; Vicente Samano; Francis X Tavares; Kevin J Wells-Knecht; Lois L Wright; Hui-Qiang Q Zhou

doi:10.1016/j.bmcl.2006.10.102

Acyclic, orally bioavailable ketone-based cathepsin K inhibitors

Bioorg Med Chem Lett. 2007 Jan 1;17(1):22-7. doi: 10.1016/j.bmcl.2006.10.102. Epub 2006 Nov 17.

Authors

David G Barrett¹, John G Catalano, David N Deaton, Stacey T Long, Robert B McFadyen, Aaron B Miller, Larry R Miller, Vicente Samano, Francis X Tavares, Kevin J Wells-Knecht, Lois L Wright, Hui-Qiang Q Zhou

Affiliation

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

PMID: 17157021
DOI: 10.1016/j.bmcl.2006.10.102

Abstract

Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone.

MeSH terms

Administration, Oral
Biological Availability
Cathepsin K
Cathepsins / antagonists & inhibitors*
Cathepsins / chemistry
Crystallography, X-Ray
Cysteine Proteinase Inhibitors / administration & dosage
Cysteine Proteinase Inhibitors / chemistry*
Cysteine Proteinase Inhibitors / pharmacokinetics*
Humans
Ketones / administration & dosage
Ketones / chemistry*
Ketones / pharmacokinetics*
Protein Conformation
Structure-Activity Relationship

Substances

Cysteine Proteinase Inhibitors
Ketones
Cathepsins
CTSK protein, human
Cathepsin K