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

被引：14

作者：

Miyata, Sachiho ^{[1
]}

Kawashima, Yuji ^{[1
]}

Sakai, Miku ^{[2
]}

Matsubayashi, Masaya ^{[2
]}

Motoki, Keisuke ^{[2
]}

Miyajima, Yui ^{[1
]}

Watanabe, Yousuke ^{[2
]}

Chikamatsu, Noriko ^{[2
]}

Taniguchi, Tetsuya ^{[2
]}

Tokuyama, Ryukou ^{[1
]}

机构：

[1] FUJI YAKUHIN CO LTD, Res Lab 1, Nishi Ku, 1-32-3 Nishi Omiya, Saitama, Japan

[2] FUJI YAKUHIN CO LTD, Res Lab 2, Nishi Ku, Saitama 6361, Japan

来源：

SCIENTIFIC REPORTS | 2021年 / 11卷 / 01期

关键词：

FARNESOID-X-RECEPTOR; NONALCOHOLIC FATTY LIVER; BILE-ACID; NUCLEAR RECEPTOR; OBETICHOLIC ACID; TARGETED DISRUPTION; FXR AGONISTS; MOUSE MODEL; TGR5; STEATOHEPATITIS;

D O I：

10.1038/s41598-021-88493-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

共 60 条

[1] Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064 [J].

Akwabi-Ameyaw, Adwoa ;

Bass, Jonathan Y. ;

Caldwell, Richard D. ;

Caravella, Justin A. ;

Chen, Lihong ;

Creech, Katrina L. ;

Deaton, David N. ;

Jones, Stacey A. ;

Kaldor, Istvan ;

Liu, Yaping ;

Madauss, Kevin P. ;

Marr, Harry B. ;

McFadyen, Robert B. ;

Miller, Aaron B. ;

Navas, Frank, III ;

Parks, Derek J. ;

Spearing, Paul K. ;

Todd, Dan ;

Williams, Shawn P. ;

Wisely, G. Bruce .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (15) :4339-4343

[2]

[Anonymous], INDIGO BIOSCIENCES H

[3] Beyond Bile Acids: Targeting Farnesoid X Receptor (FXR) with Natural and Synthetic Ligands [J].

Carotti, Andrea ;

Marinozzi, Maura ;

Custodi, Chiara ;

Cerra, Bruno ;

Pellicciari, Roberto ;

Gioiello, Antimo ;

Macchiarulo, Antonio .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2014, 14 (19) :2129-2142

[4] Quaternary Centers by Nickel-Catalyzed Cross-Coupling of Tertiary Carboxylic Acids and (Hetero)Aryl Zinc Reagents [J].

Chen, Tie-Gen ;

Zhang, Haolin ;

Mykhailiuk, Pavel K. ;

Merchant, Rohan R. ;

Smith, Courtney A. ;

Qin, Tian ;

Baran, Phil S. .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2019, 58 (08) :2454-2458

[5]

Douglas K. L., 2017, Farnesoid X Receptor Agonist and Uses Thereof, Patent No. [WO2017/049176, 2017049176]

[6]

Douglas K. L., 2018, Patent No. [WO2018/170165, 2018170165]

[7] A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR [J].

Downes, M ;

Verdecia, MA ;

Roecker, AJ ;

Hughes, R ;

Hogenesch, JB ;

Kast-Woelbern, HR ;

Bowman, ME ;

Ferrer, JL ;

Anisfeld, AM ;

Edwards, PA ;

Rosenfeld, JM ;

Alvarez, JGA ;

Noel, JP ;

Nicolaou, KC ;

Evans, RM .

MOLECULAR CELL, 2003, 11 (04) :1079-1092

[8] Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists [J].

Duan, Hongliang ;

Ning, Mengmeng ;

Chen, Xiaoyan ;

Zou, Qingan ;

Zhang, Liming ;

Feng, Ying ;

Zhang, Lina ;

Leng, Ying ;

Shen, Jianhua .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (23) :10475-10489

[9] Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance [J].

Fang, Sungsoon ;

Suh, Jae Myoung ;

Reilly, Shannon M. ;

Yu, Elizabeth ;

Osborn, Olivia ;

Lackey, Denise ;

Yoshihara, Eiji ;

Perino, Alessia ;

Jacinto, Sandra ;

Lukasheva, Yelizaveta ;

Atkins, Annette R. ;

Khvat, Alexander ;

Schnab, Bernd ;

Yu, Ruth T. ;

Brenner, David A. ;

Coulter, Sally ;

Liddle, Christopher ;

Schoonjans, Kristina ;

Olefsky, Jerrold M. ;

Saltiel, Alan R. ;

Downes, Michael ;

Evans, Ronald M. .

NATURE MEDICINE, 2015, 21 (02) :159-165

[10] The liver and the waistline: Fifty years of growth [J].

Farrell, Geoffrey C. .

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 2009, 24 :S105-S118

← 1 2 3 4 5 6 →