2. Academic Validation
  3. Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Orally Bioavailable and Brain Penetrant Mutant IDH1 Inhibitors

Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Orally Bioavailable and Brain Penetrant Mutant IDH1 Inhibitors

  • ACS Med Chem Lett. 2018 Jun 11;9(7):746-751. doi: 10.1021/acsmedchemlett.8b00182.
Qian Zhao 1,  James R Manning 1,  James Sutton 1,  Abran Costales 1,  Martin Sendzik 1 2,  Cynthia M Shafer 1,  Julian R Levell 2,  Gang Liu 2,  Thomas Caferro 2,  Young Shin Cho 2,  Mark Palermo 2,  Gregg Chenail 2,  Julia Dooley 2,  Brian Villalba 2,  Ali Farsidjani 2,  Jinyun Chen 2,  Stephanie Dodd 2,  Ty Gould 2,  Guiqing Liang 2,  Kelly Slocum 2,  Minying Pu 2,  Brant Firestone 2,  Joseph Growney 2,  Tycho Heimbach 2,  Raymond Pagliarini 2
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, California 94608, United States.
  • 2 Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
PMID: 30034612 DOI: 10.1021/acsmedchemlett.8b00182
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.

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