2. Academic Validation
  3. Discovery of a GPR40 Superagonist: The Impact of Aryl Propionic Acid α-Fluorination

Discovery of a GPR40 Superagonist: The Impact of Aryl Propionic Acid α-Fluorination

  • ACS Med Chem Lett. 2018 Dec 3;10(1):16-21. doi: 10.1021/acsmedchemlett.8b00444.
Hui Huang 1,  Sanath K Meegalla 1,  James C Lanter 1,  Michael P Winters 1,  Shuyuan Zhao 1,  James Littrell 1,  Jenson Qi 1,  Brian Rady 1,  Paul S Lee 1,  Jianying Liu 1,  Tonya Martin 1,  Wing W Lam 1,  Fran Xu 1,  Heng Keang Lim 1,  Thomas Wilde 1,  Jose Silva 1,  Monicah Otieno 1,  Alessandro Pocai 1,  Mark R Player 1
Affiliations

Affiliation

  • 1 Departments of Medicinal Chemistry, Cardiovascular & Metabolism in Vitro Biology, Cardiovascular & Metabolism in Vivo Pharmacology, andPreclinical Drug Safety, Janssen Research & Development, Welsh and McKean Roads,Spring House, Pennsylvania 19477-0776, United States.
PMID: 30655940 DOI: 10.1021/acsmedchemlett.8b00444
Abstract

GPR40 is a G-protein-coupled receptor which mediates fatty acid-induced glucose-stimulated Insulin secretion from pancreatic beta cells and incretion release from enteroendocrine cells of the small intestine. GPR40 full agonists exhibit superior glucose lowering compared to partial agonists in preclinical species due to increased Insulin and GLP-1 secretion, with the added benefit of promoting weight loss. In our search for potent GPR40 full agonists, we discovered a superagonist which displayed excellent in vitro potency and superior efficacy in the Gαs-mediated signaling pathway. Most synthetic GPR40 agonists have a carboxylic acid headgroup, which may cause idiosyncratic toxicities, including drug-induced-liver-injury (DILI). With a methyl group and a fluorine atom substituted at the α-C of the carboxylic acid group, 19 is not only highly efficacious in lowering glucose and body weight in rodent models but also has a low DILI risk due to its stable acylglucuronide metabolite.

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