Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists
Sachiho Miyata1, Yuji Kawashima2, Miku Sakai3
1Research Laboratory 1, FUJI YAKUHIN. CO., LTD, 1-32-3, Nishi-Omiya, Nishi-ku, Saitama City, Saitama, Japan. s-miyata@fujiyakuhin.co.jp.
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.
More Related Videos
10:51Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 15, 2013
09:21Real Time Monitoring of Intracellular Bile Acid Dynamics Using a Genetically Encoded FRET-based Bile Acid Sensor
Published on: January 4, 2016
Related Concept Videos
Drug Discovery: Overview
Drug-Receptor Interaction: Agonist
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous...
Structure-Activity Relationships and Drug Design
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
Transducer Mechanism: Nuclear Receptors
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
G Protein-coupled Receptors
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
Drug-Receptor Interactions
Several parameters, such as the drug's affinity for its receptor and its efficacy, which is its ability to activate the receptor, determine the drug's effect on the tissue....
