1429182-93-3Relevant academic research and scientific papers
Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1
Levell, Julian R.,Caferro, Thomas,Chenail, Gregg,Dix, Ina,Dooley, Julia,Firestone, Brant,Fortin, Pascal D.,Giraldes, John,Gould, Ty,Growney, Joseph D.,Jones, Michael D.,Kulathila, Raviraj,Lin, Fallon,Liu, Gang,Mueller, Arne,Van der Plas, Simon,Slocum, Kelly,Smith, Troy,Terranova, Remi,Touré, B. Barry,Tyagi, Viraj,Wagner, Trixie,Xie, Xiaoling,Xu, Ming,Yang, Fan S.,Zhou, Liping X.,Pagliarini, Raymond,Cho, Young Shin
supporting information, p. 151 - 156 (2017/03/08)
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 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 IDH1wt. 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.
3-PYRIMIDIN-4-YL-OXAZOLIDIN-2-ONES AS INHIBITORS OF MUTANT IDH
-
Page/Page column 102; 103, (2014/09/29)
The invention is directed to a formula (I), or a pharmamceutically acceptable salt thereof, wherein R1, R2a, R2b and R3-R7 are herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.
3-PYRIMIDIN-4-YL-OXAZOLIDIN-2-ONES AS INHIBITORS OF MUTANT IDH
-
Page/Page column 94, (2013/04/13)
The invention is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1-R6 are defined herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formual (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer
