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_N2 alkylation strategy and a robust process for the preparation of its phosphate prodrug <b>28</b> (BMS-986163) from parent <b>1</b> using POCl₃. A deoxyfluorination reaction employing bis­(2-methoxyethyl)­aminosulfur 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 S1P₁ 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 S1P₁ 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 sp³/sp² 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