6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol Derivatives as Efficacious Mitochondrial Uncouplers in STAM Mouse Model of Nonalcoholic Steatohepatitis
| Autor: | Joseph M. Salamoun, Stefan R. Hargett, Martina Beretta, Stephanie J. Alexopoulos, Ellen M. Olzomer, Divya P. Shah, Murray Jacob H, Webster L. Santos, Sing-Young Chen, Christopher J Garcia, Simon P. Tucker, Kyle L. Hoehn |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Chemistry Transporter Pharmacology medicine.disease 01 natural sciences Small molecule In vitro 0104 chemical sciences Bioavailability 010404 medicinal & biomolecular chemistry 03 medical and health sciences Fibrosis Drug Discovery medicine Molecular Medicine Myocyte Inner mitochondrial membrane 030304 developmental biology EC50 |
| Zdroj: | Journal of Medicinal Chemistry. 63:6203-6224 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 EC50 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|