{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Gan X"],"funding":["NIDDK NIH HHS","National Institutes of Health","NIGMS NIH HHS","U.S. Department of Education"],"pagination":["202-208"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6525014"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["62(5)"],"pubmed_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 (IC<sub>50</sub> , 1.1μM vs 0.6μM, respectively) against recombinant human TBK1. When incubated with human, rat, and mouse liver microsomes, amlexanox (1) and d<sub>2</sub> -amlexanox (5) were stable (t<sub>1/2</sub>  > 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."],"journal":["Journal of labelled compounds & radiopharmaceuticals"],"pubmed_title":["Synthesis of deuterium-labelled amlexanox and its metabolic stability against mouse, rat, and human microsomes."],"pmcid":["PMC6525014"],"funding_grant_id":["T32-GM007767","GAANN/P200A150164","T32 GM007767","R01 DK100319"],"pubmed_authors":["Showalter HD","Wilson MW","Sun D","Tesmer JJG","Gan X","Larsen SD","Saltiel AR","Wen B","Beyett TS"],"additional_accession":[]},"is_claimable":false,"name":"Synthesis of deuterium-labelled amlexanox and its metabolic stability against mouse, rat, and human microsomes.","description":"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<sub>50</sub> , 1.1μM vs 0.6μM, respectively) against recombinant human TBK1. When incubated with human, rat, and mouse liver microsomes, amlexanox (1) and d<sub>2</sub> -amlexanox (5) were stable (t<sub>1/2</sub>  > 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.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019 May","modification":"2024-02-15T12:50:04.15Z","creation":"2020-05-22T20:08:15Z"},"accession":"S-EPMC6525014","cross_references":{"pubmed":["30828860"],"doi":["10.1002/jlcr.3716"]}}