2 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 of a Potent, Selective, and Efficacious Phosphatidylinositol 3‑Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders
PI3Kδ plays an important role
controlling immune cell function and has therefore been identified
as a potential target for the treatment of immunological disorders.
This article highlights our work toward the identification of a potent,
selective, and efficacious PI3Kδ inhibitor. Through careful
SAR, the successful replacement of a polar pyrazole group by a simple
chloro or trifluoromethyl group led to improved Caco-2 permeability,
reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity
profile while maintaining potency in the CD69 hWB assay. The optimization
of the aryl substitution then identified a 4′-CN group that
improved the human/rodent correlation in microsomal metabolic stability.
Our lead molecule is very potent in PK/PD assays and highly efficacious
in a mouse collagen-induced arthritis model