2 research outputs found
Development of a Concise Multikilogram Synthesis of LPA‑1 Antagonist BMS-986020 via a Tandem Borylation–Suzuki Procedure
The process development for the synthesis
of BMS-986020 (<b>1</b>) via a palladium catalyzed tandem borylation/Suzuki
reaction
is described. Evaluation of conditions culminated in an efficient
borylation procedure using tetrahydroxydiboron followed by a tandem
Suzuki reaction employing the same commercially available palladium
catalyst for both steps. This methodology addressed shortcomings of
early synthetic routes and was ultimately used for the multikilogram
scale synthesis of the active pharmaceutical ingredient <b>1</b>. Further evaluation of the borylation reaction showed useful reactivity
with a range of substituted aryl bromides and iodides as coupling
partners. These findings represent a practical, efficient, mild, and
scalable method for borylation
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