Oxadiazolopyridine Derivatives as Efficacious Mitochondrial Uncouplers in the Prevention of Diet-Induced Obesity.

ABSTRACT: Small-molecule mitochondrial uncouplers are gaining recognition as potential therapeutics for metabolic diseases such as obesity, diabetes, and nonalcoholic steatohepatitis (NASH). Specifically, heterocycles derived from BAM15, a potent and mitochondria-selective uncoupler, have yielded promising preclinical candidates that are efficacious in animal models of obesity and NASH. In this study, we report the structure-activity relationship studies of 6-amino-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol derivatives. Using oxygen consumption rate as a readout of mitochondrial uncoupling, we established 5-hydroxyoxadiazolopyridines as mild uncouplers. In particular, SHM115, which contains a pentafluoro aniline, had an EC₅₀ value of 17 μM and exhibited 75% oral bioavailability. <

SUBMITTER: Murray JH 

PROVIDER: S-EPMC10167758 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature