Abstract
Although several potent bile acid Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1) dual agonists such as INT-767 have been reported, no non-bile acid FXR/TGR5 dual agonist has been investigated to date. Therefore, we attempted to discover potent non-bile acid FXR/TGR5 dual agonists and identified some non-bile acid FXR/TGR5 dual agonists, such as isonicotinamide derivatives in vitro assay. Compound 20p was evaluated in C57BL/6J mice, that were administered a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) consisting of 60 kcal% fat and 0.1% methionine by weight for one week. Compound 20p dose-dependently induced small heterodimer partner (SHP) mRNA and decreased cytochrome P450 7A1 (CYP7A1) in the liver at 10 and 30 mg/kg, respectively, which were used as FXR agonist markers. Compound 20p significantly increased the plasma levels of GLP-1 as a TGR5 agonist, and a high concentration of GLP-1 lowered blood glucose levels. We confirmed that compound 20p was a non-bile acid FXR/TGR5 dual agonist.
Highlights
Type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) are serious hepatic disease e vents[1]
We identified 20p (FXR EC50 = 190 nM, Emax = 28%, TGR5 EC50 = 420 nM) as a non-bile acid Farnesoid X receptor (FXR)/TGR5 dual agonist
Compound 20p was evaluated in C57BL/6 J mice, that were administered CDAHFD consisting of 60 kcal% fat and 0.1% methionine by weight for one week
Summary
Type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) are serious hepatic disease e vents[1]. Activation of FXR in the liver induces a downregulation of CYP7A1 gene transcription. Obeticholic acid (OCA, INT-747, 2) is the first steroidal FXR agonist. A proof-of-concept study reported that OCA significantly improves insulin sensitivity and reduces liver inflammation and fibrosis markers, such as alanine aminotransferase (ALT) and enhanced liver fibrosis score, in patients with type 2 diabetes and NAFLD14. It has been reported that 25 mg/day of the FXR ligand, OCA, improves NAFLD activity score (NAS) and fibrosis status in the livers of noncirrhotic, nonalcoholic steatohepatitis patients. GW4064 is a selective nonsteroidal FXR agonist[19] that significantly reduces free fatty acid and triglyceride levels in db/db m ice[20]. TGR5 agonists may have broad therapeutic applications, from the treatment of metabolic disorders to liver inflammatory diseases[25]
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