Novel and potent cyclic cyanamide-based cathepsin K inhibitors

David N Deaton; Anne M Hassell; Robert B McFadyen; Aaron B Miller; Larry R Miller; Lisa M Shewchuk; Francis X Tavares; Derril H Willard Jr; Lois L Wright

doi:10.1016/j.bmcl.2005.02.033

Novel and potent cyclic cyanamide-based cathepsin K inhibitors

Bioorg Med Chem Lett. 2005 Apr 1;15(7):1815-9. doi: 10.1016/j.bmcl.2005.02.033.

Authors

David N Deaton¹, Anne M Hassell, Robert B McFadyen, Aaron B Miller, Larry R Miller, Lisa M Shewchuk, Francis X Tavares, Derril H Willard Jr, Lois L Wright

Affiliation

¹ Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. david.n.deaton@gsk.com

PMID: 15780613
DOI: 10.1016/j.bmcl.2005.02.033

Abstract

Starting from a PDE IV inhibitor hit derived from high throughput screening of the compound collection, a key pyrrolidine cyanamide pharmacophore was identified. Modifications of the pyrrolidine ring produced enhancements in cathepsin K inhibition. An X-ray co-crystal structure of a cyanamide with cathepsin K confirmed the mode of inhibition.

MeSH terms

Animals
Cathepsin K
Cathepsins / antagonists & inhibitors*
Crystallography, X-Ray
Cyanamide / chemistry*
Cyclization
Cysteine Proteinase Inhibitors / chemical synthesis*
Cysteine Proteinase Inhibitors / pharmacology
Inhibitory Concentration 50
Pyrrolidines / chemistry
Structure-Activity Relationship

Substances

Cysteine Proteinase Inhibitors
Pyrrolidines
Cyanamide
Cathepsins
Cathepsin K
pyrrolidine