Exploration of the P2-P3 SAR of aldehyde cathepsin K inhibitors

Eric E Boros; David N Deaton; Anne M Hassell; Robert B McFadyen; Aaron B Miller; Larry R Miller; Margot G Paulick; Lisa M Shewchuk; James B Thompson; Derril H Willard Jr; Lois L Wright

doi:10.1016/j.bmcl.2004.04.084

Exploration of the P2-P3 SAR of aldehyde cathepsin K inhibitors

Bioorg Med Chem Lett. 2004 Jul 5;14(13):3425-9. doi: 10.1016/j.bmcl.2004.04.084.

Authors

Eric E Boros¹, David N Deaton, Anne M Hassell, Robert B McFadyen, Aaron B Miller, Larry R Miller, Margot G Paulick, Lisa M Shewchuk, James B Thompson, Derril H Willard Jr, Lois L Wright

Affiliation

¹ Department of Medicinal Chemistry, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA.

PMID: 15177446
DOI: 10.1016/j.bmcl.2004.04.084

Abstract

The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S2 and S3 subsites with a series of carbamate derivatized norleucine aldehydes substituted at the P2 and P3 positions afforded analogs with cathepsin K IC50s between 600 nM and 130 pM.

MeSH terms

Aldehydes / chemistry*
Aldehydes / pharmacology
Binding Sites / drug effects
Carbamates / chemistry
Cathepsin K
Cathepsins / antagonists & inhibitors*
Humans
Inhibitory Concentration 50
Norleucine / chemistry
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Aldehydes
Carbamates
Protease Inhibitors
Norleucine
Cathepsins
CTSK protein, human
Cathepsin K