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Synthesis of deuterium‐labelled amlexanox and its metabolic stability against mouse, rat, and human microsomes
Author(s) -
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.
Publication year - 2019
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.3716
Subject(s) - microsome , potency , chemistry , isopropyl , pharmacology , metabolism , deuterium , stereochemistry , biochemistry , in vitro , biology , medicinal chemistry , physics , quantum mechanics
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 (IC 50 , 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) 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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