Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors

We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.

Discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors are reported. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953), which displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a favourable pharmacokinetic and safety profile.Figure optionsDownload as PowerPoint slide