2007
DOI: 10.1021/jm070130j
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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 ha… Show more

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Cited by 87 publications
(56 citation statements)
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References 26 publications
(71 reference statements)
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“…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.…”
Section: Acute Effects Of Ffas and Gpr40 Agonist On Gdis In Islets Frmentioning
confidence: 99%
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“…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.…”
Section: Acute Effects Of Ffas and Gpr40 Agonist On Gdis In Islets Frmentioning
confidence: 99%
“…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.…”
mentioning
confidence: 99%
“…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).…”
Section: Free Fatty Acid Receptors As Therapeutic Targets For Type 2 mentioning
confidence: 99%
“…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.…”
Section: High Throughput and In Silico Screening Approaches To The DImentioning
confidence: 99%
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