Literature DB >> 28947942

Discovery of an Isothiazole-Based Phenylpropanoic Acid GPR120 Agonist as a Development Candidate for Type 2 Diabetes.

Xuqing Zhang1, Chaozhong Cai1, Zhihua Sui1, Mark Macielag1, Yuanping Wang1, Wen Yan1, Arthur Suckow1, Hong Hua1, Austin Bell1, Peter Haug1, Wilma Clapper1, Celia Jenkinson1, Joseph Gunnet1, James Leonard1, William V Murray1.   

Abstract

We have discovered a novel series of isothiazole-based phenylpropanoic acids as GPR120 agonists. Extensive structure-activity relationship studies led to the discovery of a potent GPR120 agonist 4x, which displayed good EC50 values in both calcium and β-arrestin assays. It also presented good pharmaceutical properties and a favorable PK profile. Moreover, it demonstrated in vivo antidiabetic activity in C57BL/6 DIO mice. Studies in WT and knockout DIO mice showed that it improved glucose handling during an OGTT via GPR120. Overall, 4x possessed promising antidiabetic effect and good safety profile to be a development candidate.

Entities:  

Keywords:  GPR120; phenylpropanoic acid; type 2 diabetes

Year:  2017        PMID： 28947942      PMCID： PMC5601374          DOI： 10.1021/acsmedchemlett.7b00233

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


  20 in total

1.  Cloning, expression, and pharmacological characterization of the GPR120 free fatty acid receptor from cynomolgus monkey: comparison with human GPR120 splice variants.

Authors:  Kristina Moore; Qing Zhang; Nick Murgolo; Tom Hosted; Ruth Duffy
Journal:  Comp Biochem Physiol B Biochem Mol Biol       Date:  2009-08-31       Impact factor: 2.231

2.  Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human.

Authors:  Atsuhiko Ichimura; Akira Hirasawa; Odile Poulain-Godefroy; Amélie Bonnefond; Takafumi Hara; Loïc Yengo; Ikuo Kimura; Audrey Leloire; Ning Liu; Keiko Iida; Hélène Choquet; Philippe Besnard; Cécile Lecoeur; Sidonie Vivequin; Kumiko Ayukawa; Masato Takeuchi; Kentaro Ozawa; Maithé Tauber; Claudio Maffeis; Anita Morandi; Raffaella Buzzetti; Paul Elliott; Anneli Pouta; Marjo-Riitta Jarvelin; Antje Körner; Wieland Kiess; Marie Pigeyre; Roberto Caiazzo; Wim Van Hul; Luc Van Gaal; Fritz Horber; Beverley Balkau; Claire Lévy-Marchal; Konstantinos Rouskas; Anastasia Kouvatsi; Johannes Hebebrand; Anke Hinney; Andre Scherag; François Pattou; David Meyre; Taka-aki Koshimizu; Isabelle Wolowczuk; Gozoh Tsujimoto; Philippe Froguel
Journal:  Nature       Date:  2012-02-19       Impact factor: 49.962

3.  Structure-activity relationships of GPR120 agonists based on a docking simulation.

Authors:  Qi Sun; Akira Hirasawa; Takafumi Hara; Ikuo Kimura; Tetsuya Adachi; Takeo Awaji; Masaji Ishiguro; Takayoshi Suzuki; Naoki Miyata; Gozoh Tsujimoto
Journal:  Mol Pharmacol       Date:  2010-08-04       Impact factor: 4.436

Review 4.  Effects of dietary polyunsaturated n-3 fatty acids on dyslipidemia and insulin resistance in rodents and humans. A review.

Authors:  Yolanda B Lombardo; Adriana G Chicco
Journal:  J Nutr Biochem       Date:  2005-09-08       Impact factor: 6.048

5.  Design, Synthesis, and Evaluation of Novel and Selective G-protein Coupled Receptor 120 (GPR120) Spirocyclic Agonists.

Authors:  Jason M Cox; Hong D Chu; Mariappan V Chelliah; John S Debenham; Keith Eagen; Ping Lan; Matthew Lombardo; Clare London; Michael A Plotkin; Unmesh Shah; Zhongxiang Sun; Henry M Vaccaro; Srikanth Venkatraman; Takao Suzuki; Nengxue Wang; Eric R Ashley; Alejandro Crespo; Maria Madeira; Dennis H Leung; Candice Alleyne; Aimie M Ogawa; Sarah Souza; Brande Thomas-Fowlkes; Jerry Di Salvo; Adam Weinglass; Melissa Kirkland; Michele Pachanski; Mary Ann Powles; Effie Tozzo; Taro E Akiyama; Feroze Ujjainwalla; James R Tata; Christopher J Sinz
Journal:  ACS Med Chem Lett       Date:  2016-11-17       Impact factor: 4.345

6.  Design, synthesis and SAR of a novel series of heterocyclic phenylpropanoic acids as GPR120 agonists.

Authors:  Xuqing Zhang; Chaozhong Cai; Michael Winters; Michele Wells; Mark Wall; James Lanter; Zhihua Sui; Jingyuan Ma; Aaron Novack; Imad Nashashibi; Yuanping Wang; Wen Yan; Arthur Suckow; Hong Hua; Austin Bell; Peter Haug; Wilma Clapper; Celia Jenkinson; Joseph Gunnet; James Leonard; William V Murray
Journal:  Bioorg Med Chem Lett       Date:  2017-06-12       Impact factor: 2.823

7.  Application of GPCR Structures for Modelling of Free Fatty Acid Receptors.

Authors:  Irina G Tikhonova
Journal:  Handb Exp Pharmacol       Date:  2017

8.  Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120).

Authors:  Steven M Sparks; Grace Chen; Jon L Collins; Dana Danger; Steven T Dock; Channa Jayawickreme; Stephen Jenkinson; Christopher Laudeman; M Anthony Leesnitzer; Xi Liang; Patrick Maloney; David C McCoy; David Moncol; Vincent Rash; Thomas Rimele; Padmaja Vulimiri; James M Way; Sean Ross
Journal:  Bioorg Med Chem Lett       Date:  2014-05-16       Impact factor: 2.823

9.  Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity.

Authors:  Carlos M G Azevedo; Kenneth R Watterson; Ed T Wargent; Steffen V F Hansen; Brian D Hudson; Małgorzata A Kępczyńska; Julia Dunlop; Bharat Shimpukade; Elisabeth Christiansen; Graeme Milligan; Claire J Stocker; Trond Ulven
Journal:  J Med Chem       Date:  2016-09-22       Impact factor: 7.446

10.  A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice.

Authors:  Da Young Oh; Evelyn Walenta; Taro E Akiyama; William S Lagakos; Denise Lackey; Ariane R Pessentheiner; Roman Sasik; Nasun Hah; Tyler J Chi; Jason M Cox; Mary Ann Powels; Jerry Di Salvo; Christopher Sinz; Steven M Watkins; Aaron M Armando; Heekyung Chung; Ronald M Evans; Oswald Quehenberger; Joanne McNelis; Juliane G Bogner-Strauss; Jerrold M Olefsky
Journal:  Nat Med       Date:  2014-07-06       Impact factor: 87.241
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  4 in total

Review 1.  Leveraging the Gut to Treat Metabolic Disease.

Authors:  Ruth E Gimeno; Daniel A Briere; Randy J Seeley
Journal:  Cell Metab       Date:  2020-03-17       Impact factor: 27.287

2.  GPR120/FFAR4 Pharmacology: Focus on Agonists in Type 2 Diabetes Mellitus Drug Discovery.

Authors:  Gabriele Carullo; Sarah Mazzotta; Margarita Vega-Holm; Fernando Iglesias-Guerra; José Manuel Vega-Pérez; Francesca Aiello; Antonella Brizzi
Journal:  J Med Chem       Date:  2021-04-10       Impact factor: 7.446

3.  Novel GPR120 Agonists with Improved Pharmacokinetic Profiles for the Treatment of Type 2 Diabetes.

Authors:  Guoxia Ji; Qinghua Guo; Qidi Xue; Ruifang Kong; Shiben Wang; Kang Lei; Renmin Liu; Xuekun Wang
Journal:  Molecules       Date:  2021-11-16       Impact factor: 4.411

4.  Thiazolidinedione derivatives as novel GPR120 agonists for the treatment of type 2 diabetes.

Authors:  Xuekun Wang; Guoxia Ji; Xinyu Han; Huiran Hao; Wenjing Liu; Qidi Xue; Qinghua Guo; Shiben Wang; Kang Lei; Yadi Liu
Journal:  RSC Adv       Date:  2022-02-16       Impact factor: 3.361
  4 in total

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