Identification of potent and selective MMP-13 inhibitors

Junjun Wu; Thomas S Rush 3rd; Rajeev Hotchandani; Xuemei Du; Mary Geck; Elisabeth Collins; Zhang-Bao Xu; Jerry Skotnicki; Jeremy I Levin; Frank E Lovering

doi:10.1016/j.bmcl.2005.06.019

Identification of potent and selective MMP-13 inhibitors

Bioorg Med Chem Lett. 2005 Sep 15;15(18):4105-9. doi: 10.1016/j.bmcl.2005.06.019.

Authors

Junjun Wu¹, Thomas S Rush 3rd, Rajeev Hotchandani, Xuemei Du, Mary Geck, Elisabeth Collins, Zhang-Bao Xu, Jerry Skotnicki, Jeremy I Levin, Frank E Lovering

Affiliation

¹ Department of Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.

PMID: 16005220
DOI: 10.1016/j.bmcl.2005.06.019

Abstract

A potent, selective series of MMP-13 inhibitors has been derived from a weak (3.2 microM) inhibitor that did not bear a zinc chelator. Structure-based drug design strategies were employed to append a Zn-chelating group to one end of the molecule and functionality to enhance selectivity to the other. A compound from this series demonstrated rat oral bioavailability and efficacy in a bovine articular cartilage explant model.

MeSH terms

Administration, Oral
Amino Acids / chemistry
Animals
Benzofurans / chemistry
Cartilage / drug effects
Cartilage / enzymology
Cattle
Chelating Agents / chemistry
Collagenases / chemistry
Collagenases / metabolism
Crystallography, X-Ray
Drug Design
In Vitro Techniques
Inhibitory Concentration 50
Matrix Metalloproteinase 13
Matrix Metalloproteinase Inhibitors*
Models, Molecular
Protease Inhibitors / administration & dosage
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacokinetics
Protease Inhibitors / pharmacology*
Protein Structure, Tertiary
Rats
Sensitivity and Specificity
Structure-Activity Relationship
Substrate Specificity
Zinc / metabolism

Substances

Amino Acids
Benzofurans
Chelating Agents
Matrix Metalloproteinase Inhibitors
Protease Inhibitors
Collagenases
Matrix Metalloproteinase 13
Mmp13 protein, rat
Zinc
benzofuran