Synthesis of deuterium‐labelled amlexanox and its metabolic stability against mouse, rat, and human microsomes. (3rd April 2019)

• Record Type: Journal Article
• Authors: Gan, Xinmin; Wilson, Michael W.; Beyett, Tyler S.; Wen, Bo; Sun, Duxin; Larsen, Scott D.; Tesmer, John J.G.; Saltiel, Alan R.; Showalter, Hollis D.
• Is Part Of: Journal of labelled compounds & radiopharmaceuticals. Volume 62:Number 5(2019)
• Page Start: 202
• Page End: 208
• Publication Date: 2019-04-03
• Subjects: obesity -- amlexanox -- d2‐amlexanox -- metabolites -- microsomal stability -- TBK1 kinase -- Wilkinson's catalyst; Tracers (Chemistry) -- Periodicals; Radiopharmaceuticals -- Periodicals; 615.8424
• DOI: 10.1002/jlcr.3716
• Languages: English
• ISSNs: 0362-4803

Abstract

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 derivative5 in which deuterium has been introduced into two sites of metabolism on the C‐7 isopropyl function of amlexanox. The synthesis of5 was completed in an efficient three‐step process utilizing reduction of key olefin7b to8 by Wilkinson's catalyst to provide specific incorporation of di‐deuterium across the double bond. Compound5 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 d 2 ‐amlexanox (5 ) were stable ( t 1/2 > 60 minutes) with1 showing marginally greater stability relative to5 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. Abstract : A derivative of the TBK1 inhibitor amlexanox (1 ) has been synthesized with deuterium introduced into two sites of metabolism on the C‐7 isopropyl function. d 2 ‐Amlexanox (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, 1 and5 were stable ( t 1/2 > 60 minutes) with1 showing marginally greater stability relative to5 except for rat liver microsomes.