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

Autor:	Huang C; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Fischer C; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Machacek MR; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Bogen S; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Biftu T; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Huang X; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Reutershan MH; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Otte R; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Hong Q; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Wu Z; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Yu Y; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Park M; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Chen L; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Biju P; Merck & Co., Inc., Kenilworth, New Jersey 07033, United States., Knemeyer I; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Lu P; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Kochansky CJ; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Hicks MB; Merck & Co., Inc., Rahway, New Jersey 07065 United States., Liu Y; Merck & Co., Inc., Rahway, New Jersey 07065 United States., Helmy R; Merck & Co., Inc., Rahway, New Jersey 07065 United States., Fradera X; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Donofrio A; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Close J; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Maddess ML; Merck & Co., Inc., Boston, Massachusetts 02115, United States., White C; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Sloman DL; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Sciammetta N; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Lu J; Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Gibeau C; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Simov V; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Zhang H; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Fuller P; Merck & Co., Inc., Boston, Massachusetts 02115, United States., Witter D; Merck & Co., Inc., Boston, Massachusetts 02115, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2022 Mar 28; Vol. 13 (4), pp. 734-741. Date of Electronic Publication: 2022 Mar 28 (Print Publication: 2022).
DOI:	10.1021/acsmedchemlett.2c00089
Abstrakt:	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 brain-penetrant 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. Competing Interests: The authors declare no competing financial interest. (© 2022 American Chemical Society.)
Databáze:	MEDLINE
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