Synthesis and Biological Evaluation of 3-Aryl-3-(4-phenoxy)-propionic Acid as a Novel Series of G Protein-Coupled Receptor 40 Agonists

Abstract

High-throughput screening of a subset of the J&J compound library containing the carboxylic acid functional group uncovered a bromophenyl derivative as a moderate potent GPR40 agonist. Chemical elaboration of this bromophenyl led to the discovery of a novel series of GPR40 agonists with submicromolar potency. Among them, 22 and 24 behaved as full agonists when compared to the endogenous GPR40 ligand linolenic acid in a functional Ca+2 flux assay in HEK cells expressing GPR40 receptor. Several GPR40 agonists have also demonstrated the ability to induce glucose-mediated insulin secretion in the mouse MIN6 pancreatic beta-cell line. Our data supports the hypothesis that GPR40 may play an important role in fatty acid-mediated glucose-dependent insulin secretion. Compound 22 exhibited good pharmacokinetic profile in rat and may serve as a good candidate for in vivo study and may help to determine if GPR40 agonists would be beneficial in the treatment of type II diabetes.

Selective Small-Molecule Agonists of G Protein–Coupled Receptor 40 Promote Glucose-Dependent Insulin Secretion and Reduce Blood Glucose in Mice

“…Smallmolecule agonists of GPR40 have been shown by others (23,33) to enhance GDIS in insulinoma cell lines, but it has yet to be established that activation of GPR40 with synthetic agonists would enhance GDIS in primary islets. We thus examined the acute effects of FFAs and GPR40 agonists (Cpd-B and Cpd-C) on GDIS in islets from GPR40 Ϫ/Ϫ and wild-type mice in both 1-h static incubations ( Fig.…”

“…Several naturally occurring medium-to longchain FFAs and some thiazolidinedione peroxisome proliferator-activated receptor-␥ agonists specifically activate GPR40 (27,28). Activation of GPR40 by FFAs (29 -32) or synthetic compounds (23,33) enhances insulin secretion through the amplification of intracellular calcium signaling.…”

Seven Transmembrane-spanning Receptors for Free Fatty Acids as Therapeutic Targets for Diabetes Mellitus: Pharmacological, Phylogenetic, and Drug Discovery Aspects

“…Taken together, these studies suggest that FFAR1 ligands could be useful for enhancing insulin secretion in patients with type 2 diabetes mellitus (agonists) or for blocking negative metabolic consequences of chronic overstimulation (antagonists). Because of this therapeutic potential, FFAR1 has been a target of research in the pharmaceutical industry (22,23,(32)(33)(34).…”

“…Drug discovery endeavors to date have concentrated on GPR119, for which the development of selective agonists has been reported by OSI Pharmaceuticals and Arena Pharmaceuticals (4,35), and on FFAR1 (22,23,(32)(33)(34). Modulators of GPR119 and FFAR1 have also been the object of numerous patents filed under the Patent Cooperation Treaty.…”

“…Similarly, through chemical elaboration of a bromophenyl derivative of a propanoic acid analog that resulted from high throughput screening, Johnson & Johnson identified a novel series of 3-aryl-3-(4-phenoxy)propanoic acid analogs as agonists of FFAR1 with submicromolar potencies and good pharmacokinetic profiles (32). Moreover, a number of ␤-substituted arylalkylic carboxylic acids have been recently identified by researchers at Amgen (34).…”