5-((1H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5

Adam M Gilbert; Matthew G Bursavich; Sabrina Lombardi; Katy E Georgiadis; Erica Reifenberg; Carl R Flannery; Elisabeth A Morris

doi:10.1016/j.bmcl.2006.12.020

5-((1H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5

Bioorg Med Chem Lett. 2007 Mar 1;17(5):1189-92. doi: 10.1016/j.bmcl.2006.12.020. Epub 2006 Dec 12.

Authors

Adam M Gilbert¹, Matthew G Bursavich, Sabrina Lombardi, Katy E Georgiadis, Erica Reifenberg, Carl R Flannery, Elisabeth A Morris

Affiliation

¹ Exploratory Medicinal Chemistry, Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA. [email protected]

PMID: 17210252
DOI: 10.1016/j.bmcl.2006.12.020

Abstract

A series of 5-((1H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5 (aggrecanase-2) is described. These compounds show microM functional inhibition of ADAMTS-5, and represent a new class of agents with the potential of inhibiting degradation of aggrecan, a major component of cartilage which is lost in osteoporosis. Compound 12 is noteworthy in that it has an ADAMTS-5 IC50: 1.1 microM and shows >40-fold functional selectivity over ADAMTS-4 (aggrecanase-1).

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAMTS4 Protein
ADAMTS5 Protein
Aggrecans / drug effects
Aggrecans / metabolism
Cartilage
Humans
Inhibitory Concentration 50
Osteoporosis / drug therapy
Procollagen N-Endopeptidase
Structure-Activity Relationship
Thiazolidinediones / chemical synthesis*
Thiazolidinediones / pharmacology

Substances

Aggrecans
Thiazolidinediones
ADAM Proteins
ADAMTS5 Protein
ADAMTS5 protein, human
Procollagen N-Endopeptidase
ADAMTS4 Protein
ADAMTS4 protein, human