Levell, Julian, Cho, Young, Caferro, Thomas, Chenail, Gregg, Dix, Ina, Dooley, Julie, Firestone, Brant, Fortin, Pascal, Giraldes, John, Gould, Ty, Herlihy, Kara, Hood, Tami, Kulathila, Raviraj, Lin, Fallon, Liu, Gang, Van Der Plas, Simon, Slocum, Kelly, Smith, Troy, Toure, Bakary-Barry, Wagner, Beatrix, Xie, Xiaoling, Yang, Fan, Pagliarini, Raymond, Xu, Ming and Zhou, Liping (2016) Identification and Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1. ACS Medicinal Chemistry Letters, 8 (2). pp. 151-156. ISSN 1948-5875

Abstract

High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1R132H. Synthesis of the 4 diastereomers identified the (S,S)-diastereomer (IDH125) as the most potent isomer, with reasonable cellular activity and excellent selectivity vs IDH1wt. Initial SAR exploration identified the key tolerances and potential for optimization. X-ray crystallography of IDH125 in the homodimer of IDH1R132H identified the allosteric binding site and aided the rationalization for excellent mutant selective inhibition, as well as the lack of activity vs mutant IDH2. Potency improvement and modulation of the in-vitro ADME profile identified (S)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (IDH889) with good in-vivo exposure and in-vivo activity in a mutant IDH1 mouse xenograft model.

Item Type:	Article
Date Deposited:	22 Feb 2017 00:45
Last Modified:	22 Feb 2017 00:45
URI:	https://oak.novartis.com/id/eprint/29191