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 (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.

• Authors: Xinmin Gan, Michael W Wilson, Tyler S Beyett, Bo Wen, Duxin Sun, Scott D Larsen, John J G Tesmer, Alan R Saltiel, Hollis D Showalter
• Journal: Journal of labelled compounds & radiopharmaceuticals (J Labelled Comp Radiopharm) Vol. 62 Issue 5 Pg. 202-208 (05 15 2019) ISSN: 1099-1344 [Electronic] England
• PMID: 30828860 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2019 John Wiley & Sons, Ltd.

Chemical References

• Aminopyridines
• Deuterium
• amlexanox
• Protein Serine-Threonine Kinases
• TBK1 protein, human

Topics

• Aminopyridines (chemical synthesis, chemistry, metabolism, pharmacology)
• Animals
• Chemistry Techniques, Synthetic
• Deuterium (chemistry)
• Drug Stability
• Humans
• Isotope Labeling
• Kinetics
• Mice
• Microsomes (metabolism)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Rats