Zhao, Qian, Manning, James, Sutton, James, Costales, Abran, Sendzik, Martin, Shafer, Cynthia, Levell, Julian, Liu, Gang, Caferro, Thomas, Cho, Young, Palermo, Mark, Chenail, Gregg, Dooley, Julie, Villalba, Brian, Farsidjani, Alireza, Chen, Jinyun, Dodd, Stephanie, Gould, Ty, Liang, Guiqing, Slocum, Kelly, Pu, Minying, Firestone, Brant, Growney, Joseph, Heimbach, Tycho and Pagliarini, Raymond (2018) Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Orally Bioavailable and Brain Penetrant Mutant IDH1 Inhibitors. ACS Medicinal Chemistry Letters, 9. pp. 746-751. ISSN 19485875

Abstract

Mutant isocitrate dehydrogenase 1 (IDH1) is an attractive therapeutic target for the treatment of various cancers such as AML, glioma and glioblastoma. We have evaluated 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors that bind to an allosteric, induced pocket of IDH1R132H. This letter describes SAR exploration focused on improving both the in vitro and in vivo metabolic stability of the compounds, leading to the identification of 19 as a potent and selective mutant IDH1 inhibitor that has demonstrated brain penetration and excellent oral bioavailability in rodents. In a preclinical patient-derived IDH1 mutant xenograft tumor model study, 19 efficiently inhibited the production of the biomarker, 2-HG.

Item Type:	Article
Date Deposited:	02 Aug 2018 00:45
Last Modified:	02 Aug 2018 00:45
URI:	https://oak.novartis.com/id/eprint/36100