title: Solid phase synthesis and SAR of small molecule agonists for the GPR40 receptor.
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.
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Steve.C.McKeown@gsk.com
authors.forename: Stephen C
authors.initials: SC
authors.lastname: McKeown
authors.forename: David F
authors.initials: DF
authors.lastname: Corbett
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Goetz
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Littleton
authors.forename: Eric
authors.initials: E
authors.lastname: Bigham
authors.forename: Celia P
authors.initials: CP
authors.lastname: Briscoe
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peat
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
authors.forename: Deirdre M B
authors.initials: DM
authors.lastname: Hickey
mesh_terms: D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D007202:Indicators and Reagents; D008024:Ligands; D011485:Protein Binding; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; C473035:G-protein-coupled receptor 40, rat; D007202:Indicators and Reagents; D008024:Ligands; D043562:Receptors, G-Protein-Coupled