Solid phase synthesis and SAR of small molecule agonists for the GPR40 receptor

Stephen C McKeown; David F Corbett; Aaron S Goetz; Thomas R Littleton; Eric Bigham; Celia P Briscoe; Andrew J Peat; Steve P Watson; Deirdre M B Hickey

doi:10.1016/j.bmcl.2006.12.084

Solid phase synthesis and SAR of small molecule agonists for the GPR40 receptor

Bioorg Med Chem Lett. 2007 Mar 15;17(6):1584-9. doi: 10.1016/j.bmcl.2006.12.084. Epub 2007 Jan 4.

Authors

Stephen C McKeown¹, David F Corbett, Aaron S Goetz, Thomas R Littleton, Eric Bigham, Celia P Briscoe, Andrew J Peat, Steve P Watson, Deirdre M B Hickey

Affiliation

¹ Molecular Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Steve.C.McKeown@gsk.com

PMID: 17240142
DOI: 10.1016/j.bmcl.2006.12.084

Abstract

The discovery, synthesis and structure-activity relationship (SAR) of novel carboxylic acid agonists for GPR40 are described. Aryl propionic acid 1, identified from a high throughput screen, was selected for chemical exploration. Compound 2 was identified as our lead molecule through efficient solid phase combinatorial array chemistry and had an attractive in vitro and in vivo pharmacokinetic profile in rat. These ligands may prove useful in establishing a role for GPR40 in insulin regulation.

MeSH terms

Animals
Biological Availability
CHO Cells
Carboxylic Acids / chemical synthesis*
Carboxylic Acids / pharmacokinetics
Carboxylic Acids / pharmacology*
Chemical Phenomena
Chemistry, Physical
Cricetinae
Cricetulus
Drug Evaluation, Preclinical
Indicators and Reagents
Ligands
Protein Binding
Rats
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship

Substances

Carboxylic Acids
G-protein-coupled receptor 40, rat
Indicators and Reagents
Ligands
Receptors, G-Protein-Coupled