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Updated: Jan 28, 2026

Quantitative Determination of De Novo Fatty Acid Synthesis in Brown Adipose Tissue Using Deuterium Oxide
Published on: May 12, 2023
Synthesis of deuterium-labelled amlexanox and its metabolic stability against mouse, rat, and human microsomes
Xinmin Gan1,2, Michael W Wilson1,2, Tyler S Beyett3,4
1Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
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 (t1/2 > 60 minutes) with 1 showing marginally greater stability relative to 5 except for rat liver microsomes. These data show that incorporating deuterium into two sites of metabolism does not majorly suppress Cyp-mediated metabolism relative to amlexanox.
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