Design and Identification of a GPR40 Full Agonist (SCO-267) Possessing a 2-Carbamoylphenyl Piperidine Moiety.
2020
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 1, 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 4a, which had improved potency for GPR40 and high lipophilicity.
We replaced the hydrophobic moiety with N-alkyl-N-aryl benzamides to lower the lipophilicity and restrict
the N-alkyl moieties to the presumed lipophilic pocket
using the intramolecular π–π stacking of cis-preferential N-alkyl-N-aryl benzamide. Among these,
orally available (3S)-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 (SCO-267) effectively stimulated insulin secretion
and GLP-1 release and ameliorated glucose tolerance in diabetic rats
via GPR40 full agonism.
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