化学
葡萄糖醛酸化
羧酸
葡萄糖醛酸
生物化学
吲哚试验
立体化学
酶
新陈代谢
微粒体
作者
Tim Ryder,Matthew F. Calabrese,Gregory S. Walker,Kimberly O. Cameron,Allan R. Reyes,Kris A. Borzilleri,Jake Delmore,Russell Miller,Ravi G. Kurumbail,Jessica Ward,Daniel W. Kung,Janice A. Brown,David J. Edmonds,Heather Eng,Angela Wolford,Amit S. Kalgutkar
标识
DOI:10.1021/acs.jmedchem.8b00807
摘要
Studies on indole-3-carboxylic acid derivatives as direct activators of human adenosine monophosphate-activated protein kinase (AMPK) α1β1γ1 isoform have culminated in the identification of PF-06409577 (1), PF-06885249 (2), and PF-06679142 (3) as potential clinical candidates. Compounds 1–3 are primarily cleared in animals and humans via glucuronidation. Herein, we describe the biosynthetic preparation, purification, and structural characterization of the glucuronide conjugates of 1–3. Spectral characterization of the purified glucuronides M1, M2, and M3 indicated that they were acyl glucuronide derivatives. In vitro pharmacological evaluation revealed that all three acyl glucuronides retained selective activation of β1-containing AMPK isoforms. Inhibition of de novo lipogenesis with representative parent carboxylic acids and their respective acyl glucuronide conjugates in human hepatocytes demonstrated their propensity to activate cellular AMPK. Cocrystallization of the AMPK α1β1γ1 isoform with 1–3 and M1–M3 provided molecular insights into the structural basis for AMPK activation by the glucuronide conjugates.
科研通智能强力驱动
Strongly Powered by AbleSci AI