Discovery of a Highly Selective JAK2 Inhibitor BMS-911543for the Treatment of Myeloproliferative Neoplasms

摘要

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole >1 led to the discovery of a clinical candidate, BMS-911543 (>11), with excellent kinome selectivity, in vivo PD activity, and safety profile.