Design and Identification of a GPR40 Full Agonist (<b>SCO-267</b>) Possessing a 2-Carbamoylphenyl Piperidine Moiety

Abstract

GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic β-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and incretin, both of which are the pivotal regulators of glycemic control. Therefore, a GPR40 agonist is an attractive target for the treatment of type 2 diabetes mellitus. Using the reported biaryl derivative <b>1</b>, we shifted the hydrophobic moiety to the terminal aryl ring and replaced the central aryl ring with piperidine, generating 2-(4,4-dimethylpentyl)phenyl piperidine <b>4a</b>, which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with <i>N</i>-alkyl-<i>N</i>-aryl benzamides to lower the lipophilicity and restrict the <i>N</i>-alkyl moieties to the presumed lipophilic pocket using the intramolecular π-π stacking of cis-preferential <i>N</i>-alkyl-<i>N</i>-aryl benzamide. Among these, orally available (3<i>S</i>)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (<b>SCO-267</b>) effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism.