Exhaustive Deuterium Editing Study of 1,4-Benzodiazepine-2,5-dione Derivatives

Key words

deuterium editing - MetID studies - cancer

Significance

Deuterium substitution is an emerging strategy to alter the metabolic profile of pharmaceutical compounds amongst other drug properties. In this work, Zheng and Liu exhaustively investigate the effect of deuterium substitution at multiple metabolic sites of protein translation inhibitor 1. These studies culminated in 15-deuterated derivative 3f which exhibited improved clearance and demonstrated efficacy in vivo. Impressively, GMP-grade 3f was produced for IND-filing with >99.5% isotopic enrichment.

Comment

CYP3A4 was found to be the primary metabolic enzyme for 1. The major metabolic pathways for 1 are oxidative dealkylation of the diethylamide, oxidation of the 3,5-dimethylbenzene, and oxidation of the methoxy functional groups. Additionally, it was found that the N-4 methyl group played a key role in mediating oxidative deethylation of 1. An exhaustive study was performed investigating the effect of selective deuteration on the intrinsic clearance and primary site of metabolism. These studies lead to identification of 3f, which exhibited 9.3-fold reduction in intrinsic clearance. ­Albumin-bound nanoparticles of 3f demonstrated an 8.33 h and 9.36 h t _1/2 in bone marrow and tumor tissue, respectively, and exhibited dose-dependent inhibition in mouse models of various cancer types. Synthesis of GMP-grade 3f was accomplished with >99.5% isotopic enrichment in 51% yield.

Publikationsverlauf

Artikel online veröffentlicht:
13. September 2024