The identification of beta-hydroxy carboxylic acids as selective MMP-12 inhibitors

Ian P Holmes; Simon Gaines; Steve P Watson; Olivier Lorthioir; Adam Walker; Suzanne J Baddeley; Shane Herbert; Danielle Egan; Máire A Convery; Onkar M P Singh; Jeffrey W Gross; John M Strelow; Robert H Smith; Augustin J Amour; David Brown; Stephen L Martin

doi:10.1016/j.bmcl.2009.07.155

The identification of beta-hydroxy carboxylic acids as selective MMP-12 inhibitors

Bioorg Med Chem Lett. 2009 Oct 1;19(19):5760-3. doi: 10.1016/j.bmcl.2009.07.155. Epub 2009 Aug 6.

Authors

Ian P Holmes¹, Simon Gaines, Steve P Watson, Olivier Lorthioir, Adam Walker, Suzanne J Baddeley, Shane Herbert, Danielle Egan, Máire A Convery, Onkar M P Singh, Jeffrey W Gross, John M Strelow, Robert H Smith, Augustin J Amour, David Brown, Stephen L Martin

Affiliation

¹ GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

PMID: 19703773
DOI: 10.1016/j.bmcl.2009.07.155

Abstract

A new class of selective MMP-12 inhibitors have been identified via high throughput screening. Crystallization with MMP-12 confirmed the mode of binding and allowed initial optimization to be carried out using classical structure based design.

MeSH terms

Animals
Binding Sites
Carboxylic Acids / chemical synthesis
Carboxylic Acids / chemistry*
Carboxylic Acids / pharmacology
Crystallography, X-Ray
Drug Design
Guinea Pigs
Humans
Matrix Metalloproteinase 12 / metabolism
Matrix Metalloproteinase Inhibitors*
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Carboxylic Acids
Matrix Metalloproteinase Inhibitors
Protease Inhibitors
Matrix Metalloproteinase 12