Diminishing GSH-Adduct Formation of Tricyclic Diazepine-based Mutant IDH1 Inhibitors

Abstract

Mutant isocitrate dehydrogenase 1 (IDH1) has been identified as an attractive oncology target for which >70% of grade II and III gliomas and ∼10% of acute myeloid leukemia (AML) harbor somatic IDH1 mutations. These mutations confer a neomorphic gain of function, leading to the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). We identified and developed a potent, selective, and orally bioavailable brainpenetrant tricyclic diazepine scaffold that inhibits mutant IDH1. During the course of in vitro metabolism studies, GSH-adduct metabolites were observed. The hypothesis for GSH-adduct formation was driven by the electron-rich nature of the tricyclic core. Herein, we describe our efforts to reduce the electron-rich nature of the core. Ultimately, a strategy focused on core modifications to block metabolic hot spots coupled with substitution pattern changes (C8 N → C linked) led to the identification of new tricyclic analogues with minimal GSH-adduct formation across species while maintaining an overall balanced profile.

Process Development of a Tricyclic Diazepine-Based IDH1 Mutant Inhibitor

“…The desired product 2 was isolated as an off-white solid (9.09 kg, 48.8 mol, 73% over two steps). Characterization was consistent with previously reported data …”

“…After stirring for 20 min, 20 mL of n -heptane was added over 1 h. The mixture was stirred for 30 min and then filtered, and the desired product was dried under a nitrogen bag to afford 1 as a white solid (1.21 g, 77%). Characterization was consistent with previously reported data …”

“…Characterization was consistent with previously reported data. 14 General Procedure for the Selective Acylation of Dihydropyridobenzodiazepines. To a solution/suspension of tricyclic dihydropyridobenzodiazepine core (e.g., 20, 1 equiv) in dioxane (15 volumes) at room temperature was added the acid chloride (1.03 equiv) under nitrogen.…”

“…Characterization was consistent with previously reported data. 14 Preliminary Through-Process Development to 1. To a round-bottom flask fitted with an overhead stirrer were charged 23 (16.15 g, 32.3 mmol, 1 equiv), 39 (9.91 g, 88 wt %, 37.1 mmol.…”

“…The molecule features a tricyclic dihydropyridobenzodiazepine core wherein the zigzag morpholine group at C8 and cyclohexyl acid at the N6 were found to be important to maximize IDH1 MUT binding. 14 Tricycle 1 was pharmacologically active in an orthotopic glioma model 15 and overall had favorable physiochemical properties. It was selected for progression toward clinical trials, and a route capable of supporting kilogram-scale deliveries was required.…”