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

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 IDH1. This Letter describes SAR exploration focused on improving both the and metabolic stability of the compounds, leading to the identification of 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, efficiently inhibited the production of the biomarker 2-HG.

One‐Step Synthesis of 3,4‐Disubstituted 2‐Oxazolidinones by Base‐Catalyzed CO2 Fixation and Aza‐Michael Addition

“…[55] In the following step, the mixed carbamate B reacts with Michael acceptor 1 by nucleophilic substitution of bromine to form the acyclic O-alkyl carbamate C and TMG·HBr.I ntermediate C was identified by using N-methylaniline as as ubstrate, leadingt o the isolation of acyclic carbamate 3r.N ext, highly soluble Cs 2 CO 3 regenerates TMG by deprotonation. The equilibrium is driven by precipitation of Cs salts, as was observed in control experiments presented in Ta ble 1( entries [11][12][13][14]. In transition state D,i ti ss hown how TMG catalyzes the cyclization by protont ransfer [56] and enolates tabilization.…”

“…One group of compounds that meets both of these criteria is the 2‐oxazolidinones, a type of five‐membered cyclic carbamates. They are particularly attractive synthetic targets due to their wide‐ranging biological activity and central role in several state‐of‐the‐art drugs, including antibiotics and anti‐cancer drugs . Consequently, the 2‐oxazolidinone core can be seen as a promising “isostere”, a replacement of conventionally used (flat aromatic) structures in biological environments; it is a saturated, nitrogen‐containing heterocycle with a tunable structure.…”

“…In the ab-sence of TMG, the yield of 3a was significantly decreased (46 %, entry 10), which was comparable to entries 6a nd 7, suggesting triethylamine and DMAP had no catalytic effect. Other inorganic bases gave inferiory ields, even with tetrabutylammoniumi odide (TBAI) or CsBr as phase-transfer catalysts (entries [11][12][13][14]. These results indicate that Cs 2 CO 3 is superior,b ecause it has ab etter solubility than other inorganic bases.…”

3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2α (HIF-2α) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma

“…One extreme example is all- cis 1,2,3,4,5,6-hexafluorocyclohexane, a facial polarized ring reported to be one of the most polar aliphatic molecules ever measured . It was also reported that compounds with fluoro substitution two or three carbons away from an oxygen atom tend to have decreased lipophilicity. , The increased polarity of PT2977 is likely due to the combination effects of fluorine atoms in close vicinity to the alcohol, and the high molecular dipole created by two vicinal electronegative fluorine atoms with cis -configuration. The decreased lipophilicity translates to significantly reduced plasma protein binding.…”

Genetic Abnormalities, Clonal Evolution, and Cancer Stem Cells of Brain Tumors

“…In another study, Kapinja et al used a brain-penetrant mutant IDH1 inhibitor (MRK-A) and explored its antitumor activity on the growth or animal survival of mice bearing either a patient-derived GB10 glioma xenograft or BT142 xenograft and observed a prolongation of the survival only of mice bearing the BT142 glioma [401]. Recent studies have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as potent mutant IDH1 inhibitors for in vivo modulation of 2-HG and brain penetration, reporting the identification of two compounds, IDH-305 [402] and compound 9 [403], both suitable for clinical studies. Five different IDH inhibitors are under evaluation in glioma patients, including the two IDH1 inhibitors AG-120 and AG-881, the IDH2 inhibitor AG-221, the pan-mutant IDH inhibitor BAY1436032, and the IDH1 inhibitor IDH-305 to be evaluated in phase 2 studies in grade II or III gliomas with IDH1 mutation that have progressed after observation or radiation therapy [404].…”