Acyclic cyanamide-based inhibitors of cathepsin K

David G Barrett; David N Deaton; Anne M Hassell; Robert B McFadyen; Aaron B Miller; Larry R Miller; J Alan Payne; Lisa M Shewchuk; Derril H Willard Jr; Lois L Wright

doi:10.1016/j.bmcl.2005.04.032

Acyclic cyanamide-based inhibitors of cathepsin K

Bioorg Med Chem Lett. 2005 Jun 15;15(12):3039-43. doi: 10.1016/j.bmcl.2005.04.032.

Authors

David G Barrett¹, David N Deaton, Anne M Hassell, Robert B McFadyen, Aaron B Miller, Larry R Miller, J Alan Payne, Lisa M Shewchuk, Derril H Willard Jr, Lois L Wright

Affiliation

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

PMID: 15896958
DOI: 10.1016/j.bmcl.2005.04.032

Abstract

Conversion of the proline-derived cyanamide lead to an acyclic cyanamide capable of forming an additional hydrogen bond with cathepsin K resulted in a large increase in inhibitory activity. An X-ray structure of a co-crystal of a cyanamide with cathepsin K confirmed the enzyme interaction. Furthermore, a representative acyclic cyanamide inhibitor 6r was able to attenuate bone resorption in the rat calvarial model.

MeSH terms

Animals
Binding Sites
Bone Resorption
Cathepsin B / antagonists & inhibitors
Cathepsin H
Cathepsin K
Cathepsin L
Cathepsins / antagonists & inhibitors*
Crystallography, X-Ray
Cyanamide / chemistry*
Cysteine Endopeptidases
Cysteine Proteinase Inhibitors / chemical synthesis
Cysteine Proteinase Inhibitors / pharmacology*
Disease Models, Animal
Humans
Hydrogen Bonding
Inhibitory Concentration 50
Models, Molecular
Molecular Structure
Osteogenesis / drug effects*
Protein Binding
Rats
Recombinant Proteins / antagonists & inhibitors
Structure-Activity Relationship

Substances

Cysteine Proteinase Inhibitors
Recombinant Proteins
Cyanamide
Cathepsins
Cysteine Endopeptidases
Cathepsin B
CTSL protein, human
Cathepsin L
Ctsl protein, rat
CTSH protein, human
Cathepsin H
Ctsh protein, rat
CTSK protein, human
Cathepsin K
Ctsk protein, rat