Discovery of a novel class of pyridine derivatives that selectively inhibits mutant Isocitrate dehydrogenase 2

Abstract

Current paper presents synthesis and Structure-Activity Relationship of pyridine derivatives as inhibitors of mutant isocitrate dehydrogenase 2 (IDH2). A series of 2,4,6-trisubsitituted pyridine derivatives have been prepared and evaluated in vitro. Among these compounds, 14n exhibited excellent inhibition activity with the IC₅₀ of 54.6 nM, which is approximately 1-fold improvement compared to drug candidate AG-221 (Enasidenib) that is in Phase III trial. Exquisite selectivity of 14n for IDH2 R140Q mutant isoform was demonstrated by the poor activity against the wild-type IDH1 and IDH2.

This article is protected by copyright. All rights reserved.

Thirty-six 2,4,6-trisubsitituted pyridine derivatives have been prepared and evaluated in vitro. Among these compounds, 14n exhibited excellent inhibition activity with the IC₅₀ of 54.6 nM, which is approximately 1-fold improvement compared to drug candidate AG-221 (Enasidenib) that is in Phase III trial.

http://ift.tt/2hYRXDm