Literature DB >> 26819665

Discovery of a Potent and Orally Efficacious TGR5 Receptor Agonist.

Sameer Agarwal1, Amit Patil1, Umesh Aware1, Prashant Deshmukh1, Brijesh Darji1, Santosh Sasane1, Kalapatapu V V M Sairam1, Priyanka Priyadarsiny1, Poonam Giri1, Harilal Patel1, Suresh Giri1, Mukul Jain1, Ranjit C Desai1.   

Abstract

TGR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. The 2-thio-imidazole derivative 6g was identified as a novel, potent, and selective TGR5 agonist (hTGR5 EC50 = 57 pM, mTGR5 = 62 pM) with a favorable pharmacokinetic profile. The compound 6g was found to have potent glucose lowering effects in vivo during an oral glucose tolerance test in DIO C57 mice with ED50 of 7.9 mg/kg and ED90 of 29.2 mg/kg.

Entities:  

Keywords:  GLP1 secretion; GPBAR1; GPR 131; TGR5; TGR5 agonist; diabetes

Year:  2015        PMID： 26819665      PMCID： PMC4716599          DOI： 10.1021/acsmedchemlett.5b00323

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  25 in total

Review 1.  Animal models of non-insulin-dependent diabetes.

Authors:  E Shafrir
Journal:  Diabetes Metab Rev       Date:  1992-10

Review 2.  Significance of protein binding in pharmacokinetics and pharmacodynamics.

Authors:  Stephan Schmidt; Daniel Gonzalez; Hartmut Derendorf
Journal:  J Pharm Sci       Date:  2010-03       Impact factor: 3.534

3.  The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor κ light-chain enhancer of activated B cells (NF-κB) in mice.

Authors:  Yan-Dong Wang; Wei-Dong Chen; Donna Yu; Barry M Forman; Wendong Huang
Journal:  Hepatology       Date:  2011-08-11       Impact factor: 17.425

Review 4.  Patented TGR5 modulators: a review (2006 - present).

Authors:  Antimo Gioiello; Emiliano Rosatelli; Roberto Nuti; Antonio Macchiarulo; Roberto Pellicciari
Journal:  Expert Opin Ther Pat       Date:  2012-10-06       Impact factor: 6.674

Review 5.  Animal models of diabetes mellitus: physiology and pathology.

Authors:  R H Bell; R J Hye
Journal:  J Surg Res       Date:  1983-11       Impact factor: 2.192

6.  Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.

Authors:  Mitsuhiro Watanabe; Sander M Houten; Chikage Mataki; Marcelo A Christoffolete; Brian W Kim; Hiroyuki Sato; Nadia Messaddeq; John W Harney; Osamu Ezaki; Tatsuhiko Kodama; Kristina Schoonjans; Antonio C Bianco; Johan Auwerx
Journal:  Nature       Date:  2006-01-08       Impact factor: 49.962

Review 7.  TGR5: an emerging bile acid G-protein-coupled receptor target for the potential treatment of metabolic disorders.

Authors:  Atul Tiwari; Pranab Maiti
Journal:  Drug Discov Today       Date:  2009-02-25       Impact factor: 7.851

8.  Discovery of trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as potent, orally bioavailable TGR5 (GPBAR1) agonists: structure-activity relationships, lead optimization, and chronic in vivo efficacy.

Authors:  Dean P Phillips; Wenqi Gao; Yang Yang; Guobao Zhang; Isabelle K Lerario; Thomas L Lau; Jiqing Jiang; Xia Wang; Deborah G Nguyen; B Ganesh Bhat; Carol Trotter; Heather Sullivan; Gustav Welzel; Jannine Landry; Yali Chen; Sean B Joseph; Chun Li; W Perry Gordon; Wendy Richmond; Kevin Johnson; Angela Bretz; Badry Bursulaya; Shifeng Pan; Peter McNamara; H Martin Seidel
Journal:  J Med Chem       Date:  2014-04-04       Impact factor: 7.446

9.  TGR5-mediated bile acid sensing controls glucose homeostasis.

Authors:  Charles Thomas; Antimo Gioiello; Lilia Noriega; Axelle Strehle; Julien Oury; Giovanni Rizzo; Antonio Macchiarulo; Hiroyasu Yamamoto; Chikage Mataki; Mark Pruzanski; Roberto Pellicciari; Johan Auwerx; Kristina Schoonjans
Journal:  Cell Metab       Date:  2009-09       Impact factor: 27.287

10.  Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.

Authors:  Ralph A Defronzo
Journal:  Diabetes       Date:  2009-04       Impact factor: 9.461
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  13 in total

1.  Differential action of TGR5 agonists on GLP-2 secretion and promotion of intestinal adaptation in a piglet short bowel model.

Authors:  Sen Lin; Barbara Stoll; Jason Robinson; Jose J Pastor; Juan C Marini; Ignacio R Ipharraguerre; Bolette Hartmann; Jens J Holst; Stephanie Cruz; Patricio Lau; Oluyinka Olutoye; Zhengfeng Fang; Douglas G Burrin
Journal:  Am J Physiol Gastrointest Liver Physiol       Date:  2019-03-28       Impact factor: 4.052

2.  Ursolic acid activates the TGR5 receptor to enhance GLP-1 secretion in type 1-like diabetic rats.

Authors:  Shih-Hsiang Lo; Yingxiao Li; Kai Chun Cheng; Chiang-Shan Niu; Juei-Tang Cheng; Ho-Shan Niu
Journal:  Naunyn Schmiedebergs Arch Pharmacol       Date:  2017-07-30       Impact factor: 3.000

3.  Discovery of Orally Efficacious Tetrahydrobenzimidazoles as TGR5 Agonists for Type 2 Diabetes.

Authors:  Xuqing Zhang; Mark Wall; Zhihua Sui; Jack Kauffman; Cuifen Hou; Cailin Chen; Fuyong Du; Thomas Kirchner; Yin Liang; Dana L Johnson; William V Murray; Keith Demarest
Journal:  ACS Med Chem Lett       Date:  2017-04-21       Impact factor: 4.345

4.  Identification of an Orally Efficacious GPR40/FFAR1 Receptor Agonist.

Authors:  Sameer Agarwal; Santosh Sasane; Prashant Deshmukh; Bhadresh Rami; Debdutta Bandyopadhyay; Poonam Giri; Suresh Giri; Mukul Jain; Ranjit C Desai
Journal:  ACS Med Chem Lett       Date:  2016-09-21       Impact factor: 4.345

Review 5.  TGR5, Not Only a Metabolic Regulator.

Authors:  Cong Guo; Wei-Dong Chen; Yan-Dong Wang
Journal:  Front Physiol       Date:  2016-12-26       Impact factor: 4.566

6.  The Dietary Furocoumarin Imperatorin Increases Plasma GLP-1 Levels in Type 1-Like Diabetic Rats.

Authors:  Lin-Yu Wang; Kai-Chun Cheng; Yingxiao Li; Chiang-Shan Niu; Juei-Tang Cheng; Ho-Shan Niu
Journal:  Nutrients       Date:  2017-10-30       Impact factor: 5.717

Review 7.  Improving glucose and lipids metabolism: drug development based on bile acid related targets.

Authors:  Hanchen Shen; Lili Ding; Mehdi Baig; Jingyan Tian; Yang Wang; Wendong Huang
Journal:  Cell Stress       Date:  2021-01-05

8.  Intestinally-targeted TGR5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect.

Authors:  Hua Cao; Zhi-Xiang Chen; Kai Wang; Meng-Meng Ning; Qing-An Zou; Ying Feng; Yang-Liang Ye; Ying Leng; Jian-Hua Shen
Journal:  Sci Rep       Date:  2016-06-24       Impact factor: 4.379

9.  Investigation of triamterene as an inhibitor of the TGR5 receptor: identification in cells and animals.

Authors:  Yingxiao Li; Kai Chun Cheng; Chiang-Shan Niu; Shih-Hsiang Lo; Juei-Tang Cheng; Ho-Shan Niu
Journal:  Drug Des Devel Ther       Date:  2017-04-05       Impact factor: 4.162

10.  Identification of degradation impurity of TGR5 receptor agonist-ZY12201 by LC-MS technique during force degradation study.

Authors:  Chandrakant Sojitra; Chintan Dholakia; Padmaja Sudhakar; Kumar K Singh; Sameer Agarwal
Journal:  SN Appl Sci       Date:  2021-05-25
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