6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol Derivatives as Efficacious Mitochondrial Uncouplers in STAM Mouse Model of Nonalcoholic Steatohepatitis

Abstract

Small molecule mitochondrial uncouplers have recently garnered great interest for their potential in treating nonalcoholic steatohepatitis (NASH). In this study, we report the structure−activity relationship profiling of a 6-amino[1,2,5]oxadiazolo [3,4-b]pyrazin-5-ol core, which utilizes the hydroxy moiety as the proton transporter across the mitochondrial inner membrane. We demonstrate that a wide array of substituents is tolerated with this novel scaffold that increased cellular metabolic rates in vitro using changes in oxygen consumption rate as a readout. In particular, compound SHS4121705 (12i) displayed an EC 50 of 4.3 μM in L6 myoblast cells and excellent oral bioavailability and liver exposure in mice. In the STAM mouse model of NASH, administration of 12i at 25 mg kg −1 day −1 lowered liver triglyceride levels and improved liver markers such as alanine aminotransferase, NAFLD activity score, and fibrosis. Importantly, no changes in body temperature or food intake were observed. As potential treatment of NASH, mitochondrial uncouplers show promise for future development.

Serendipitous Discovery of a Highly Active and Selective Resistance-Modifying Agent for Colistin-Resistant Gram-Negative Bacteria

“…In addition, compound 1 is also readily hydrolyzed to the hydroxyl analogue 4 under basic aqueous condition. 34 Mass spectrometry analysis of the commercial compound confirmed our hypothesis and detected the mass of both compounds. Therefore, we synthesized and purified these two compounds using their, respectively, optimized procedures.…”

“…Therefore, we synthesized and purified these two compounds using their, respectively, optimized procedures. 33 , 34 …”

Furazans in Medicinal Chemistry

“…277 The compound is well-tolerated in vivo, producing therapeutic responses in models of kidney injury, 277 diet-induced obesity, 278 insulin resistance (diabetes) 279 and fatty liver disease. 280 SAR studies determined the furazanopyrazine is essential, providing the requisite balance of lipophilic character and acidity, 281,282 and replacement with other heterocycles led to decreased activity 283 (Figure 29).…”

“…The advanced lead SHS4121705 is currently being investigated by Continuum Biosciences as a treatment for nonalcoholic steatohepatitis. 282 A series of P-gp ligands have been disclosed by Colabufo and coworkers as positron emission topography (PET) imaging tools 285 and cotherapeutic agents to mitigate effluxrelated drug resistance 286 (Figure 30). The addition of a pendant furazan to the established pharmacophore MC70 significantly enhanced potency and selectivity (MDR1/ MRP1); the furazan moiety forms an additional H-bonding interaction with Gln-195.…”

“…The compound is well-tolerated in vivo , producing therapeutic responses in models of kidney injury, diet-induced obesity, insulin resistance (diabetes) and fatty liver disease . SAR studies determined the furazanopyrazine is essential, providing the requisite balance of lipophilic character and acidity, , and replacement with other heterocycles led to decreased activity (Figure ). Optimization of the activity, physical properties and PK profile identified hydroxy-substituted furazanopyrazines as efficient mitochondrial uncouplers (Table ).…”