Synthesis of deuterium-labelled amlexanox and its metabolic stability against mouse, rat, and human microsomes.

ABSTRACT: As part of a program toward making analogues of amlexanox (1), currently under clinical investigation for the treatment of type 2 diabetes and obesity, we have synthesized derivative 5 in which deuterium has been introduced into two sites of metabolism on the C-7 isopropyl function of amlexanox. The synthesis of 5 was completed in an efficient three-step process utilizing reduction of key olefin 7b to 8 by Wilkinson's catalyst to provide specific incorporation of di-deuterium across the double bond. Compound 5 displayed nearly equivalent potency to amlexanox (IC₅₀ , 1.1μM vs 0.6μM, respectively) against recombinant human TBK1. When incubated with human, rat, and mouse liver microsomes, amlexanox (1) and d₂ -amlexanox (5) were stable (t_1/2  > 60 minutes) wit

SUBMITTER: Gan X 

PROVIDER: S-EPMC6525014 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature