3 research outputs found
Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug
This paper describes the efficient
scale-up synthesis of the potent
negative allosteric glutamate N2B (GluN2B) inhibitor <b>1</b> (BMS-986169), which relies upon a stereospecific S<sub>N</sub>2
alkylation strategy and a robust process for the preparation of its
phosphate prodrug <b>28</b> (BMS-986163) from parent <b>1</b> using POCl<sub>3</sub>. A deoxyfluorination reaction employing bisÂ(2-methoxyethyl)Âaminosulfur
trifluoride (Deoxo-Fluor) is also used to stereospecifically introduce
a fluorine substituent. The optimized routes have been demonstrated
to provide APIs suitable for toxicological studies in vivo
Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P<sub>1</sub> Receptor Modulator in Clinical Trials
Clinical
validation of S1P receptor modulation therapy was achieved
with the approval of fingolimod (Gilenya, <b>1</b>) as the first
oral therapy for relapsing remitting multiple sclerosis. However, <b>1</b> causes a dose-dependent reduction in the heart rate (bradycardia),
which occurs within hours after first dose. We disclose the identification
of clinical compound BMS-986104 (<b>3d</b>), a novel S1P<sub>1</sub> receptor modulator, which demonstrates ligand-biased signaling
and differentiates from <b>1</b> in terms of cardiovascular
and pulmonary safety based on preclinical pharmacology while showing
equivalent efficacy in a T-cell transfer colitis model
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