GPR40 Activator 1

GPR40 Activator 1 is a potent GPR40 activator for treatment of type 2 diabetes.

GPR40 mediates potential positive effects of a saturated fatty acid enriched diet on bone.[Pubmed:27611773]

Mol Nutr Food Res. 2017 Feb;61(2).

SCOPE: The stimulation of the free fatty acid receptor G-protein coupled receptor (GPR) 40 by GW9508 prevents bone loss by inhibiting osteoclast activity, both in vitro and in vivo. Here, we questioned whether the stimulation of the GPR40 receptor by dietary fatty acids may lead to the same beneficial effect on bone. METHODS AND RESULTS: We investigated (i) the impact of a fatty acid enriched diet (high-fat diet [HFD]) on bone health in C57/BL6 female mice depending on (ii) the estrogen status (ovariectomy) and (iii) the genotype (GPR40(+/+) or GPR40(-/-) ). Bone mineral density (BMD), body composition, weight, inflammation and bone remodeling parameters were monitored. HFD decreased BMD in HFD-SH-GPR40(+/+) mice but OVX failed to further impact BMD in HFD-OVX-GPR40(+/+) mice, while additional bone loss was observed in HFD-OVX-GPR40(-/-) animals. These data suggest that when stimulated by fatty acid enriched diets GPR40 contributes to counteract ovariectomy-induced bone alteration. The sparing effect is supported by the modulation of both the osteoprotegerin/receptor activator of nuclear factor kappa-B ligand (OPG/RANKL) ratio in blood stream and the expression level of inflammatory markers in adipose tissues. Bone preservation by GPR40 stimulation is dependent on the presence of long-chain saturated fatty acids. CONCLUSION: GPR40 contributes to counter ovariectomy-induced bone loss in a context of saturated fatty acid enrichment.

G Protein-coupled Receptor 40 (GPR40) and Peroxisome Proliferator-activated Receptor gamma (PPARgamma): AN INTEGRATED TWO-RECEPTOR SIGNALING PATHWAY.[Pubmed:26105050]

J Biol Chem. 2015 Aug 7;290(32):19544-57.

Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have been widely used to treat type 2 diabetes mellitus. However, knowledge of PPARgamma signaling remains incomplete. In addition to PPARgamma, these drugs also activate G protein-coupled receptor 40 (GPR40), a Galphaq-coupled free fatty acid receptor linked to MAPK networks and glucose homeostasis. Notably, p38 MAPK activation has been implicated in PPARgamma signaling. Here, rosiglitazone (RGZ) activation of GPR40 and p38 MAPK was found to boost PPARgamma-induced gene transcription in human endothelium. Inhibition or knockdown of p38 MAPK or expression of a dominant negative (DN) p38 MAPK mutant blunted RGZ-induced PPARgamma DNA binding and reporter activity in EA.hy926 human endothelial cells. GPR40 inhibition or knockdown, or expression of a DN-Galphaq mutant likewise blocked activation of both p38 MAPK and PPARgamma reporters. Importantly, RGZ induction of PPARgamma target genes in primary human pulmonary artery endothelial cells (PAECs) was suppressed by knockdown of either p38 MAPK or GPR40. GPR40/PPARgamma signal transduction was dependent on p38 MAPK activation and induction of PPARgamma co-activator-1 (PGC1alpha). Silencing of p38 MAPK or GPR40 abolished the ability of RGZ to induce phosphorylation and expression of PGC1alpha in PAECs. Knockdown of PGC1alpha, its essential activator SIRT1, or its binding partner/co-activator EP300 inhibited RGZ induction of PPARgamma-regulated genes in PAECs. RGZ/GPR40/p38 MAPK signaling also led to EP300 phosphorylation, an event that enhances PPARgamma target gene transcription. Thus, GPR40 and PPARgamma can function as an integrated two-receptor signal transduction pathway, a finding with implications for rational drug development.

[Current status of clinical development of novel anti-diabetic drugs].[Pubmed:25812383]

Nihon Rinsho. 2015 Mar;73(3):517-22.

Clinical development of novel antidiabetic drugs, such as GK activator, GPR40 agonist, GPR119 agonist, 11beta-HSD1 inhibitor and trelagliptin, has been progressing over the world. Especially, GK activator, GPR40 agonist, GPR119 agonist and 112-HSD1 inhibitor have unique action mechanism compared to existing drugs. GK activator potentiates glucose-stimulated insulin secretion from beta cells and stimulates glucose uptake into the liver. GPR40 agonists and GPR119 agonist stimulate glucose-dependent insulin secretion from beta cells. 11beta-HSD1 inhibitor reduces the conversion of cortisone to cortisol. Trelagliptin is a long acting dipeptidyl peptidase-4(DPP-4) inhibitor and a once-weekly treatment by trelagliptin would improve the drug adherence of patients. This article focuses on these new and emerging diabetes agents.

Discovery of Chromane Propionic Acid Analogues as Selective Agonists of GPR120 with in Vivo Activity in Rodents.[Pubmed:28105282]

ACS Med Chem Lett. 2016 Dec 6;8(1):96-101.

GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor (GPCR) that has been identified as a target for possible treatment of type 2 diabetes. A selective activator of GPR120 containing a chromane scaffold has been designed, synthesized, and evaluated in vivo. Results of these efforts suggest that chromane propionic acid 18 is a suitable tool molecule for further animal studies. Compound 18 is selective over the closely related target GPR40 (FFAR1), has a clean off-target profile, demonstrates suitable pharmacokinetic properties, and has been evaluated in wild-type/knockout GPR120 mouse oGTT studies.

PPARgamma signaling and emerging opportunities for improved therapeutics.[Pubmed:27268145]

Pharmacol Res. 2016 Sep;111:76-85.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism, endothelial function and inflammation. Rosiglitazone (RGZ) and other thiazolidinedione (TZD) synthetic ligands of PPARgamma are insulin sensitizers that have been used for the treatment of type 2 diabetes. However, undesirable side effects including weight gain, fluid retention, bone loss, congestive heart failure, and a possible increased risk of myocardial infarction and bladder cancer, have limited the use of TZDs. Therefore, there is a need to better understand PPARgamma signaling and to develop safer and more effective PPARgamma-directed therapeutics. In addition to PPARgamma itself, many PPARgamma ligands including TZDs bind to and activate G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1. GPR40 signaling activates stress kinase pathways that ultimately regulate downstream PPARgamma responses. Recent studies in human endothelial cells have demonstrated that RGZ activation of GPR40 is essential to the optimal propagation of PPARgamma genomic signaling. RGZ/GPR40/p38 MAPK signaling induces and activates PPARgamma co-activator-1alpha, and recruits E1A binding protein p300 to the promoters of target genes, markedly enhancing PPARgamma-dependent transcription. Therefore in endothelium, GPR40 and PPARgamma function as an integrated signaling pathway. However, GPR40 can also activate ERK1/2, a proinflammatory kinase that directly phosphorylates and inactivates PPARgamma. Thus the role of GPR40 in PPARgamma signaling may have important implications for drug development. Ligands that strongly activate PPARgamma, but do not bind to or activate GPR40 may be safer than currently approved PPARgamma agonists. Alternatively, biased GPR40 agonists might be sought that activate both p38 MAPK and PPARgamma, but not ERK1/2, avoiding its harmful effects on PPARgamma signaling, insulin resistance and inflammation. Such next generation drugs might be useful in treating not only type 2 diabetes, but also diverse chronic and acute forms of vascular inflammation such as atherosclerosis and septic shock.