2 research outputs found
Discovery of 5‑Chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1<i>H</i>)‑one (BMS-903452), an Antidiabetic Clinical Candidate Targeting GPR119
G-protein-coupled receptor 119 (GPR119)
is expressed predominantly in pancreatic β-cells and in enteroendocrine
cells in the gastrointestinal tract. GPR119 agonists have been shown
to stimulate glucose-dependent insulin release by direct action in
the pancreas and to promote secretion of the incretin GLP-1 by action
in the gastrointestinal tract. This dual mechanism of action has generated
significant interest in the discovery of small molecule GPR119 agonists
as a potential new treatment for type 2 diabetes. Herein, we describe
the discovery and optimization of a new class of pyridone containing
GPR119 agonists. The potent and selective BMS-903452 (<b>42</b>) was efficacious in both acute and chronic in vivo rodent models
of diabetes. Dosing of <b>42</b> in a single ascending dose
study in normal healthy humans showed a dose dependent increase in
exposure and a trend toward increased total GLP-1 plasma levels
Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists
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 sp<sup>3</sup>/sp<sup>2</sup> character of the chemotype,
we identified BMS-986118 (compound <b>4</b>), which showed potent
and selective GPR40 agonist activity <i>in vitro</i>. <i>In vivo</i>, compound <b>4</b> demonstrated insulinotropic
efficacy and GLP-1 secretory effects resulting in improved glucose
control in acute animal models