Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists.

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.

Discovery of Dotinurad (FYU-981), a New Phenol Derivative with Highly Potent Uric Acid Lowering Activity.

To derive new uricosuric agents, novel phenol derivatives were synthesized to overcome the disadvantages of benzbromarone (BBR), attributed by its structural features. Herein, we report the discovery of new phenol derivatives with a 1,1-dioxo-1,2-dihydro-3H-1,3-benzothiazole scaffold. The selected compound 11 (dotinurad, FYU-981) demonstrated remarkable inhibitory activity on uric acid uptake by primary human renal proximal tubule epithelial cells (RPTECs) and URAT1-mediated uric acid transport, with weak inhibitory activity against mitochondrial respiration. Dotinurad also displayed favorable pharmacokinetic profiles and higher potency in decreasing uric acid than BBR did in Cebus monkeys. Dotinurad has been approved as a new uricosuric medicine in Japan. Our strategy, which focuses on the structural features resulting in unfavorable effects, could be applied to the future developments of other drugs with disadvantages, particularly those having a bis-aryl ketone structure.