YH18968, a Novel 1,2,4-Triazolone G-Protein Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes Mellitus

Han, Taedong; Lee, Byoung Moon; Park, Yoo Hoi; Lee, Dong Hoon; Choi, Hyun Ho; Lee, Taehoon; Kim, Hakwon

doi:10.4062/biomolther.2018.011

Cited by 12 publications

(7 citation statements)

References 27 publications

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“…Activation of GPR119 can increase the release of plasma GLP-1 in rodents and humans ( Chu et al, 2008 ; Hansen et al, 2011 ; Katz et al, 2011 ; Lan et al, 2012 ; Mandøe et al, 2015 ; Han et al, 2018 ; Matsumoto et al, 2018 ). Since GLP-1R activation has been shown to modulate EtOH consumption ( Shirazi et al, 2013 ; Vallöf et al, 2016 ), we first investigated whether activation of GPR119 alters EtOH intake and preference, as well as water intake and body weight, using two different GPR119 agonists, AR231453 (3 mg/kg) or APD668 (6 mg/kg) ( Figures 1A–D ).…”

Section: Resultsmentioning

confidence: 99%

“…From this effort, GPR119 emerged as a promising therapeutic target for the development of orally active, non-peptide, small-molecule agonists to treat type 2 diabetes and obesity ( Koole et al, 2010 ; Yoshida et al, 2010 ; Semple et al, 2011 , 2012 ; Melancon et al, 2012 ; Hothersall et al, 2015 ; Spasov et al, 2017 ; Fang et al, 2020a ). Administration of GPR119 agonists has been shown to increase plasma GLP-1 and insulin, resulting in improved glucose homeostasis in rodents and humans ( Chu et al, 2008 ; Hansen et al, 2011 ; Katz et al, 2011 ; Mandøe et al, 2015 ; Han et al, 2018 ; Matsumoto et al, 2018 ). Here, we tested two different synthetic GPR119 agonists.…”

Section: Discussionmentioning

confidence: 99%

“…GPR119 is expressed in limited tissues, including the pancreatic islets and gastrointestinal tract. Activation of GPR119 via both direct actions on pancreatic β-cells and indirect actions on intestinal L-cells results in increased glucose-dependent insulin release and increased gene expression of proglucagon, a biosynthetic precursor of GLP-1, with subsequent release of endogenous GLP-1, glucose-dependent insulinotropic peptide, neurotensin, and peptide YY, leading to improvement of glucose tolerance in rodents and humans ( Overton et al, 2006 ; Chu et al, 2007 , 2008 ; Hansen et al, 2011 ; Katz et al, 2011 ; Lan et al, 2012 ; Chepurny et al, 2013 ; Mandøe et al, 2015 ; Hassing et al, 2016 ; Han et al, 2018 ; Matsumoto et al, 2018 ). Its restricted tissue distribution, relative selectivity in enhancing GLP-1 release, and tolerability of its agonists have made GPR119 an attractive therapeutic target for developing orally bioavailable agonists for type 2 diabetes treatment ( Terauchi et al, 2018 ; Yang et al, 2018 ), and potentially for other related disorders.…”

Section: Introductionmentioning

confidence: 99%

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Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

et al. 2020

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Alcohol use disorder (AUD) is a chronic relapsing condition characterized by compulsive alcohol-seeking behaviors, with serious detrimental health consequences. Despite high prevalence and societal burden, available approved medications to treat AUD are limited in number and efficacy, highlighting a critical need for more and novel pharmacotherapies. Glucagon-like peptide-1 (GLP-1) is a gut hormone and neuropeptide involved in the regulation of food intake and glucose metabolism via GLP-1 receptors (GLP-1Rs). GLP-1 analogs are approved for clinical use for diabetes and obesity. Recently, the GLP-1 system has been shown to play a role in the neurobiology of addictive behaviors, including alcohol seeking and consumption. Here we investigated the effects of different pharmacological manipulations of the GLP-1 system on escalated alcohol intake and preference in male Wistar rats exposed to intermittent access 2-bottle choice of 10% ethanol or water. Administration of AR231453 and APD668, two different agonists of G-protein receptor 119, whose activation increases GLP-1 release from intestinal L-cells, did not affect voluntary ethanol intake. By contrast, injections of either liraglutide or semaglutide, two long-acting GLP-1 analogs, potently decreased ethanol intake. These effects, however, were transient, lasting no longer than 48 h. Semaglutide, but not liraglutide, also reduced ethanol preference on the day of injection. As expected, both analogs induced a reduction in body weight. Co-administration of exendin 9-39, a GLP-1R antagonist, did not prevent liraglutide- or semaglutide-induced effects in this study. Injection of exendin 9-39 alone, or blockade of dipeptidyl peptidase-4, an enzyme responsible for GLP-1 degradation, via injection of sitagliptin, did not affect ethanol intake or preference. Our findings suggest that among medications targeting the GLP-1 system, GLP-1 analogs may represent novel and promising pharmacological tools for AUD treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

et al. 2020

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“…The tachyphylaxis is reported in several GPR119 agonists such as GSK1292263 and JNJ‐38431055 . In clinical trials, GSK1292263 did not increase blood active GLP‐1 secretion and failed to control blood glucose levels .…”

Section: Discussionmentioning

confidence: 99%

Chronic treatment of JTP‐109192, a novel G‐protein coupled receptor 119 agonist, improves metabolic abnormalities in Zucker Fatty rats

Tadaki

Sasase

Fukuda

et al. 2019

Clin Exp Pharma Physio

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G‐protein coupled receptor 119 (GPR119) expression in pancreatic β‐cells and intestinal L cells is a potential therapeutic target for treating type 2 diabetes. A natural GPR119 agonist oleoylethanolamide is well known to enhance a glucose‐stimulated insulin secretion (GSIS) and glucagon‐like peptide‐1 (GLP‐1) secretion by elevating intracellular cAMP levels. In the present study, a glucose lowering effect of the GPR119 agonist, JTP‐109192 leading to improvement of insulin sensitivity was examined in Zucker Fatty (ZF) rats. We investigated the in vitro effects of JTP‐109192 on GSIS in the rat pancreatic β‐cell line (INS1E) cells and on GLP‐1 secretion in the murine enteroendocrine cell line (GLUTag) cells. We also investigated the effect of JTP‐109192 on GSIS in Sprague‐Dawley (SD) rats with single administration and its effect on glucose metabolism in ZF rats with repeated administration once daily for about 6 weeks. After repeated administration, the hyperinsulinaemic euglycaemic glucose clamp test was performed to evaluate insulin sensitivity. JTP‐109192 increased intracellular cAMP levels (EC50 value: 3.6 nmol/L) and enhanced GSIS in the INS1E cells and GLP‐1 secretion in GLUTag cells. In SD rats, a single administration of JTP‐109192 enhanced GSIS at high blood glucose levels. The repeated administrations in ZF rats improved glucose metabolism without lack of drug efficacy (tachyphylaxis) and increased glucose infusion rates due to improvement of insulin sensitivity.

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“…G protein-coupled receptor 119 (GPR119) is a member of class A (rhodopsin-type) GPCR family, with highly expressed in pancreatic b-cells and the K and L cells of the gastrointestinal tract [7][8][9] . Activation of GPR119 increases the intracellular cyclic AMP (cAMP) level, which in turn directly stimulate the glucose-dependent insulin secretion and regulate glucagon-like peptide 1 (GLP-1), leading to improve the glucose tolerance in T2DM patients [10][11][12][13][14] . In addition, GPR119 agonists showed b-cells function preservation, which is also an important role in current T2DM therapy [15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists

Yuan

Zhang

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimisation of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound 10 and 15 demonstrated the potent EC 50 values (13 and 12 nM, respectively) and strong inherent activities. Moreover, significant hypoglycaemic effect of compound 15 was observed by reducing the blood glucose AUC 0-2h at the dose of 30 mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction).

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YH18968, a Novel 1,2,4-Triazolone G-Protein Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes Mellitus

Cited by 12 publications

References 27 publications

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

Chronic treatment of JTP‐109192, a novel G‐protein coupled receptor 119 agonist, improves metabolic abnormalities in Zucker Fatty rats

Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists

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