Synthesis and Activity of Small Molecule GPR40 Agonists.

Abstract

2006Carboxylic acids Q 0420Synthesis and Activity of Small Molecule GPR40 Agonists. -A variety of novel compounds, e.g. (VI) and (VII), that activate GPR40 at low nanomolar concentrations, is identified. (VI) behaves as a potent, full agonist at the GPR40 receptor with a pEC50 = 7.91. The acid itself is not critical for activity but elicits a higher agonistic response than that observed with carboxamide replacements (some yields not given).-(GARRIDO, D. M.; CORBETT, D. F.; DWORNIK, K. A.; GOETZ, A. S.; LITTLETON, T. R.; MCKEOWN, S. C.; MILLS, W. Y.; SMALLEY, T. L. J.; BRISCOE, C. P.; PEAT*, A.

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

“…Since GPCRs are involved in the regulation of insulin and glucagon secretion, they serve as potential drug targets. Several approaches have been undertaken to target GPCRs for new treatment (Garrido et al, 2006;McKeown et al, 2007).…”

Seven Transmembrane-spanning Receptors for Free Fatty Acids as Therapeutic Targets for Diabetes Mellitus: Pharmacological, Phylogenetic, and Drug Discovery Aspects

“…Molecular determinants for the recognition of linoleate and GW9508 (a synthetic agonist) (22,23) by FFAR1 were proposed on the basis of sequence comparisons, rhodopsinbased homology modeling, and mutagenesis (17,24). Our experimentally supported model suggests that ligands bind within the upper part of the helical bundle between TM3, TM4, TM5, and TM6.…”

“…Taken together, these studies suggest that FFAR1 ligands could be useful for enhancing insulin secretion in patients with type 2 diabetes mellitus (agonists) or for blocking negative metabolic consequences of chronic overstimulation (antagonists). Because of this therapeutic potential, FFAR1 has been a target of research in the pharmaceutical industry (22,23,(32)(33)(34).…”

“…Drug discovery endeavors to date have concentrated on GPR119, for which the development of selective agonists has been reported by OSI Pharmaceuticals and Arena Pharmaceuticals (4,35), and on FFAR1 (22,23,(32)(33)(34). Modulators of GPR119 and FFAR1 have also been the object of numerous patents filed under the Patent Cooperation Treaty.…”

“…The arylalkyl derivative of the propanoic acid GW9508 was identified by GlaxoSmithKline as a potent FFAR1 agonist with an EC 50 of ϳ50 nM, whereas FFAs exhibit potencies in the micromolar range (22,23,33). This compound exhibits significant selectivity against peroxisome proliferator-activated receptors, for which it exhibits potencies in the low micromolar range, and does not activate other members of the FFAR1 cluster.…”