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.
To read the full publication, click HERE.
Date of publication: 28 April 2021; Scientific Reports volume 11, Article number: 9196 (2021)
Author Information: Sachiho Miyata(1), Yuji Kawashima(1), Miku Sakai(2), Masaya Matsubayashi(2), Keisuke Motoki(2), Yui Miyajima(1), Yousuke Watanabe(2), Noriko Chikamatsu(2), Tetsuya Taniguchi(2) & Ryukou Tokuyama(1)
(1) Research Laboratory 1, FUJI YAKUHIN. CO., LTD, 1-32-3, Nishi-Omiya, Nishi-ku, Saitama City, Saitama, Japan
(2) Research Laboratory 2, FUJI YAKUHIN. CO., LTD, Nishi-ku, Iida-Shinden, Saitama City, Saitama, 636-1, Japan