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. SHM115 treatment increased the energy expenditure and lowered the body fat mass in two diet-induced obesity mouse models, including an obesity prevention model and an obesity reversal model. Taken together, our findings demonstrate the therapeutic potential of mild mitochondrial uncouplers for the prevention of diet-induced obesity.

Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis

“…Structural optimization substitutes amine group of diamine derivative with hydroxyl group, and it improves aqueous solubility and pharmacokinetic properties. Secondly, pentafluorination on aromatic ring yields the final optimized compound, SHM115 with optimal bioavailability and potent mitochondrial uncoupling activity [ 76 ]. It increases the energy expenditure in mice fed with HFD and a high-sugar Western diet ( Fig.…”

BAM15 as a mitochondrial uncoupler: a promising therapeutic agent for diverse diseases

“…BAM15 offers a compelling alternative by effectively increasing energy expenditure and reducing fat accumulation ( 5 ). Extensive research has focused on the potential of BAM15 to improve mitochondrial function, facilitate weight loss, and promote metabolic improvements ( 5 , 10 , 35 ).…”

Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation

“…In recent years, there is a resurgence of interest in the use of mitochondrial uncoupling agents for obesity treatment 25 . This interest is driven by emerging evidence from a number of animal studies showing that with precise dosing, 2,4-dinitrophenol can confer beneficial effects in metabolic diseases including obesity and T2DM, as well as in lifespan extension 26 , 27 .…”