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J Med Chem ; 61(3): 681-694, 2018 02 08.
Article in English | MEDLINE | ID: mdl-29316397

ABSTRACT

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.


Subject(s)
Drug Discovery , Pyrazoles/pharmacology , Pyrazoles/pharmacokinetics , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Biological Availability , Humans , Male , Mice , Models, Molecular , Molecular Conformation , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Pyrrolidines/chemistry
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