Design, synthesis, and biological evaluation of imidazo[4,5-b]pyridine mitochondrial uncouplers for the treatment of metabolic dysfunction-associated steatohepatitis (MASH)

Small molecule mitochondrial uncouplers have gained traction for their potential therapeutic use against metabolic dysfunction-associated steatohepatitis (MASH). Herein, we report a novel imidazo[4,5-b]pyridine scaffold derived from iterative modifications of the potent uncoupler BAM15. Our structure-activity relationship (SAR) study demonstrated that this promising scaffold has a range of tolerated substitutions that allows for the modulation of uncoupling activity and in vivo pharmacokinetic properties. Specifically, compound SHS206 displayed an EC50 of 830 nM in L6 myoblasts and, importantly, showed no cytotoxicity in vitro or adverse effects in mice up to 1000 mg/kg. SHS206 was administered orally at 100 and 300 mg/kg in a GAN mouse model of MASH and was observed to lower liver triglyceride levels while food intake, body weight, temperature, organ weights, and cholesterol levels remained unaltered. Together, these findings illuminate imidazo[4,5-b]pyridine as a promising scaffold for the future development of mitochondrial uncouplers. [Display omitted] •SAR study of imidazo[4,5-b]pyridine mitochondrial uncouplers.•Sub-micromolar potency and no cytotoxicity observed.•No adverse effects seen up to 1000 mg/kg oral dosing in mice.•Orally bioavailable SHS206 lowered liver triglycerides in GAN mouse model of MASH.