SAR studies of non-zinc-chelating MMP-13 inhibitors: improving selectivity and metabolic stability

Donghong Amy Gao; Zhaoming Xiong; Alexander Heim-Riether; Laura Amodeo; E Michael August; Xianhua Cao; Leonard Ciccarelli; Brandon K Collins; Kyle Harrington; Kathleen Haverty; Melissa Hill-Drzewi; Xiang Li; Shuang Liang; Steluta Mariana Margarit; Neil Moss; Nelamangala Nagaraja; John Proudfoot; Rene Roman; Sabine Schlyer; Lana Smith Keenan; Steven Taylor; Bernd Wellenzohn; Dieter Wiedenmayer; Jun Li; Neil A Farrow

doi:10.1016/j.bmcl.2010.07.036

SAR studies of non-zinc-chelating MMP-13 inhibitors: improving selectivity and metabolic stability

Bioorg Med Chem Lett. 2010 Sep 1;20(17):5039-43. doi: 10.1016/j.bmcl.2010.07.036. Epub 2010 Jul 15.

Affiliation

¹ Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA. amy.gao@boehringer-ingelheim.com

PMID: 20675133
DOI: 10.1016/j.bmcl.2010.07.036

Abstract

SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1' pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound.

MeSH terms

Chelating Agents / chemistry
Chelating Agents / pharmacology
Matrix Metalloproteinase Inhibitors*
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacology*
Structure-Activity Relationship
Zinc / chemistry

Substances

Chelating Agents
Matrix Metalloproteinase Inhibitors
Protease Inhibitors
Zinc