Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1

详细信息    查看全文

• 作者：Julian R. LevellThomas Caferro ; Gregg Chenail ; Ina Dix ; Julia Dooley ; Brant Firestone ; Pascal D. Fortin ; John Giraldes ; Ty Gould ; Joseph D. Growney ; Michael D. Jones ; Raviraj Kulathila ; Fallon Lin ; Gang Liu ; Arne Mueller ; Simon van der Plas ; Kelly Slocum ; Troy Smith ; Remi Terranova ; B. Barry Touré ; Viraj Tyagi ; Trixie Wagner ; Xiaoling Xie ; Ming Xu ; Fan S. Yang ; Liping X. Zhou ; Raymond Pagliarini ; Young Shin Cho
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：February 9, 2017
• 年：2017
• 卷：8
• 期：2
• 页码：151-156
• 全文大小：393K
• ISSN：1948-5875

文摘

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 IDH1<sup>R132Hsup>. Synthesis of the four separate stereoisomers identified the (S,S)-diastereomer (IDH125, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1<sup>wtsup>. Initial structure–activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood–brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.