TNP and its analogs: Modulation of IP6K and CYP3A4 inhibition.

ABSTRACT: Inositol hexakisphosphate kinase (IP6K) is an important mammalian enzyme involved in various biological processes such as insulin signalling and blood clotting. Recent analyses on drug metabolism and pharmacokinetic properties on TNP (N²-(m-trifluorobenzyl), N⁶-(p-nitrobenzyl)purine), a pan-IP6K inhibitor, have suggested that it may inhibit cytochrome P450 (CYP450) enzymes and induce unwanted drug-drug interactions in the liver. In this study, we confirmed that TNP inhibits CYP3A4 in type I binding mode more selectively than the other CYP450 isoforms. In an effort to find novel purine-based IP6K inhibitors with minimal CYP3A4 inhibition, we designed and synthesised 15 TNP analogs. Structure-activity relationship and biochemical studies, inc

SUBMITTER: Lee S 

PROVIDER: S-EPMC8667942 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature