Exploration of phenylpropanoic acids as agonists of the free fatty acid receptor 4 (FFA4): Identification of an orally efficacious FFA4 agonist

Sparks, Steven M.; Aquino, Christopher; Banker, Pierette; Collins, Jon L.; Cowan, David J.; Diaz, Caroline J.; Dock, Steven T.; Hertzog, Donald L.; Liang, Xi; Swiger, Erin; Yuen, Josephine; Chen, Grace; Jayawickreme, Channa; Nystrom, Christopher; Rash, Vincent; Rimele, Thomas J.; Roller, Shane; Ross, Seamus

doi:10.1016/j.bmcl.2017.01.034

Cited by 20 publications

(20 citation statements)

References 41 publications

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“…GPR120, which is expressed in both islet and in enteroendocrine cells, is activated by medium- and long-chain fatty acids (LCFAs) and has been extensively investigated as a drug target for treatment of obesity and type 2 diabetes due to its many effects on metabolism including increasing secretion of GLP-1 [ 28 , 29 ]. However, the exploration of this receptor as a therapeutic target has been limited by the lack of potent and selective agonist ligands without activity on GPR40 and only recently selective agonists have started to emerge [ 30 – 34 ]. We have developed a novel GPR120 specific agonist, AZ13581837, and studied its pharmacology and role in glucose metabolism in comparison to a previously published GPR120 agonist, Metabolex-36 [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…The role of GPR120 for stimulation of GLP-1 secretion has been well established in vitro [ 4 ] and was confirmed in this study in STC-1 cells, while the contribution of GPR120 activation in vivo for GLP-1 secretion is not completely elucidated. Species selectivity is a known issue for the GPR120 agonists [ 46 ] and it is only recently that compounds suitable for rodent models have been described [ 30 – 33 ]. AZ13581837 and Metabolex-36 were well suited for acute in vivo studies in mice.…”

Section: Discussionmentioning

confidence: 99%

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The acute glucose lowering effect of specific GPR120 activation in mice is mainly driven by glucagon-like peptide 1

et al. 2017

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The mechanism behind the glucose lowering effect occurring after specific activation of GPR120 is not completely understood. In this study, a potent and selective GPR120 agonist was developed and its pharmacological properties were compared with the previously described GPR120 agonist Metabolex-36. Effects of both compounds on signaling pathways and GLP-1 secretion were investigated in vitro. The acute glucose lowering effect was studied in lean wild-type and GPR120 null mice following oral or intravenous glucose tolerance tests. In vitro, in GPR120 overexpressing cells, both agonists signaled through Gαq, Gαs and the β-arrestin pathway. However, in mouse islets the signaling pathway was different since the agonists reduced cAMP production. The GPR120 agonists stimulated GLP-1 secretion both in vitro in STC-1 cells and in vivo following oral administration. In vivo GPR120 activation induced significant glucose lowering and increased insulin secretion after intravenous glucose administration in lean mice, while the agonists had no effect in GPR120 null mice. Exendin 9–39, a GLP-1 receptor antagonist, abolished the GPR120 induced effects on glucose and insulin following an intravenous glucose challenge. In conclusion, GLP-1 secretion is an important mechanism behind the acute glucose lowering effect following specific GPR120 activation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The acute glucose lowering effect of specific GPR120 activation in mice is mainly driven by glucagon-like peptide 1

et al. 2017

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“…For example, Adams et al [54] reported a chromane propionic acid-based agonist series where specific members are at least 300-fold more selective for both human and mouse FFA4 compared with FFA1. Similarly, Sparks et al [55] described a phenylpropanoic acid series with an exemplar compound showing between 40- and 130-fold selectivity over FFA1 across human, mouse, and rat orthologues.…”

Section: Synthetic Agonists For Ffa4mentioning

confidence: 96%

“…However, not all of the more recently described ligands are suitable for in vivo studies due to poor pharmacokinetic and pharmacodynamic properties [56] . By contrast, although not currently available from commercial suppliers, phenylpropanoic acid ‘compound 29’ [55] , nonacidic sulfonamide ‘compound 34’ [57] , and chromane propionic acid ‘compound 18’ [54] have each been used for rodent in vivo studies to explore glucose handing and aspects of regulation of insulin sensitivity. In each case, these have provided clear support for an important role of FFA4 in the regulation of glucose homeostasis.…”

Section: Synthetic Agonists For Ffa4mentioning

confidence: 99%

FFA4/GPR120: Pharmacology and Therapeutic Opportunities

Milligan

Álvarez-Curto

Hudson

et al. 2017

Trends in Pharmacological Sciences

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Free Fatty Acid receptor 4 (FFA4), also known as GPR120, is a G-protein-coupled receptor (GPCR) responsive to long-chain fatty acids that is attracting considerable attention as a potential novel therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Although no clinical studies have yet been initiated to assess efficacy in this indication, a significant number of primary publications and patents have highlighted the ability of agonists with potency at FFA4 to improve glucose disposition and enhance insulin sensitivity in animal models. However, the distribution pattern of the receptor suggests that targeting FFA4 may also be useful in other conditions, ranging from cancer to lung function. Here, we discuss and contextualise the basis for these ideas and the results to support these conclusions.

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“…Phenylpropanoic acid is a convenient structure for the synthesis of many targeted medicinal agents with hypoglycemic action [11]. In particular, substituted phenylpropanoic acids are agonists of receptors FFA4 [12], peroxisome proliferator-activated receptors (PPARs) [13] and protein tyrosine phosphatase 1B (PTP1B) inhibitors [14].…”

Section: Introductionmentioning

confidence: 99%

Bornyl Derivatives of p-(Benzyloxy)Phenylpropionic Acid: In Vivo Evaluation of Antidiabetic Activity

et al. 2020

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A series of bornyl derivatives of p-(benzyloxy)phenylpropionic acid were prepared, and their hypoglycemic activities were examined by an oral glucose tolerance test in mice. The results of this test revealed two compounds, 1 and 3, that can reduce the blood level of glucose similarly to reference compound vildagliptin. Both compounds were tested in an experiment on mice with metabolic disorders: the C57BL/6Ay strain. Along with hypoglycemic properties, the two compounds showed different abilities to correct lipid metabolism disorders. In silico prediction revealed that the studied substances are most likely bifunctional multitarget hypoglycemic compounds whose mechanism of action is based on a pronounced reduction in insulin resistance and a strong incretin-mimetic effect. The difference in the size of effects of these compounds on biochemical parameters of blood in the experiment on C57BL/6Ay mice was in good agreement with the computational prediction of the priority ranking of biological targets for these compounds. These results indicate that bornyl derivatives of p-(benzyloxy)phenylpropionic acid have a good potential as new agents for diabetes mellitus treatment due to their hypoglycemic and lipid-normalizing properties.

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Exploration of phenylpropanoic acids as agonists of the free fatty acid receptor 4 (FFA4): Identification of an orally efficacious FFA4 agonist

Cited by 20 publications

References 41 publications

The acute glucose lowering effect of specific GPR120 activation in mice is mainly driven by glucagon-like peptide 1

The acute glucose lowering effect of specific GPR120 activation in mice is mainly driven by glucagon-like peptide 1

FFA4/GPR120: Pharmacology and Therapeutic Opportunities

Bornyl Derivatives of p-(Benzyloxy)Phenylpropionic Acid: In Vivo Evaluation of Antidiabetic Activity

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