Novel N-substituted 2-phenyl-1-sulfonylamino-cyclopropane carboxylates as selective ADAMTS-5 (Aggrecanase-2) inhibitors

Makoto Shiozaki; Katsuya Maeda; Tomoya Miura; Yosuke Ogoshi; Julia Haas; Andrew M Fryer; Ellen R Laird; Nicole M Littmann; Steven W Andrews; John A Josey; Takayuki Mimura; Yuichi Shinozaki; Hiromi Yoshiuchi; Takashi Inaba

doi:10.1016/j.bmcl.2009.02.024

Novel N-substituted 2-phenyl-1-sulfonylamino-cyclopropane carboxylates as selective ADAMTS-5 (Aggrecanase-2) inhibitors

Bioorg Med Chem Lett. 2009 Mar 15;19(6):1575-80. doi: 10.1016/j.bmcl.2009.02.024. Epub 2009 Feb 11.

Authors

Makoto Shiozaki¹, Katsuya Maeda, Tomoya Miura, Yosuke Ogoshi, Julia Haas, Andrew M Fryer, Ellen R Laird, Nicole M Littmann, Steven W Andrews, John A Josey, Takayuki Mimura, Yuichi Shinozaki, Hiromi Yoshiuchi, Takashi Inaba

Affiliation

¹ Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.

PMID: 19243944
DOI: 10.1016/j.bmcl.2009.02.024

Abstract

A series of N-substituted sulfonylamino-alkanecarboxylate ADAMTS-5 (Aggrecanase-2) inhibitors has been synthesized and the in vitro enzyme SAR is discussed. This report is the first example of carboxylate-based ADAMTS-5 inhibitors which show strong potency of IC(50)<0.1muM with excellent selectivity over MMP-1 and TACE.

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAMTS5 Protein
Carboxylic Acids / chemistry
Drug Design
Humans
Inhibitory Concentration 50
Models, Chemical
Molecular Conformation
Molecular Structure
Osteoarthritis / drug therapy
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / pharmacology
Protein Structure, Tertiary
Structure-Activity Relationship

Substances

Carboxylic Acids
Protease Inhibitors
ADAM Proteins
ADAMTS5 Protein
ADAMTS5 protein, human