TRC210258, a novel TGR5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity

Shitalkumar P Zambad, Davinder Tuli, Anoop Mathur, Sameer A Ghalsasi, Anita R Chaudhary, Shailesh Deshpande, Ramesh C Gupta, Vijay Chauthaiwale, Chaitanya DuttTorrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, IndiaBackground: Patients with diabesity have a significantly increa...

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Autores principales:	Zambad SP, Tuli D, Mathur A, Ghalsasi SA, Chaudhary AR, Deshpande S, Gupta RC, Chauthaiwale V, Dutt C
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2013
Materias:	Specialties of internal medicine RC581-951
Acceso en línea:	https://doaj.org/article/0b3c46f8db6a4fa4898be37d7654f04c
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spelling	oai:doaj.org-article:0b3c46f8db6a4fa4898be37d7654f04c2021-12-02T09:09:26ZTRC210258, a novel TGR5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity1178-7007https://doaj.org/article/0b3c46f8db6a4fa4898be37d7654f04c2013-12-01T00:00:00Zhttp://www.dovepress.com/trc210258-a-novel-tgr5-agonist-reduces-glycemic-and-dyslipidemic-cardi-a15350https://doaj.org/toc/1178-7007 Shitalkumar P Zambad, Davinder Tuli, Anoop Mathur, Sameer A Ghalsasi, Anita R Chaudhary, Shailesh Deshpande, Ramesh C Gupta, Vijay Chauthaiwale, Chaitanya DuttTorrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, IndiaBackground: Patients with diabesity have a significantly increased risk of developing cardiovascular disease. Therefore, therapy addressing the multiple metabolic abnormalities linked with diabesity and leading to further reduction of cardiovascular risk is highly desirable. Activation of the TGR5 receptor holds therapeutic potential for diabesity. In the present study, we evaluated the efficacy of TRC210258, a novel TGR5 agonist, in clinically relevant animal models of diabesity.Methods: A novel small molecule, TRC210258 (N-(4-chlorophenyl)-2-(4-fluoro phenoxy)-N-methylimidazo (1, 2-a) pyrimidine-3-carboxamide), was synthesized. The in vitro TGR5 receptor activation potential of TRC210258 was assessed by cyclic adinosine monophosphate (cAMP) assay and cAMP-responsive element reporter assay using cells overexpressing the human TGR5 receptor. The effect of TRC210258 on glucagon-like peptide-1 release was evaluated in vitro using a human enteroendocrine cell line. The effect of TRC210258 on energy expenditure and glycemic control was evaluated in high-fat diet-induced obese mice. Additionally, the effect of TRC210258 on dyslipidemic parameters was determined in high fat-fed hamsters.Results: TRC210258 demonstrated potent TGR5 agonist activity, with enhanced glucagon-like peptide-1 release and energy expenditure. Treatment with TRC210258 resulted in better glycemic control and improved parameters of dyslipidemia such as plasma triglyceride, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol levels. Treatment with TRC210258 also improved emerging dyslipidemic cardiovascular risk parameters, including remnant cholesterol and triglyceride clearance.Conclusion: This study highlights the potential of TRC210258, a novel TGR5 agonist, to improve dyslipidemic cardiovascular risk beyond glycemic control in patients with type 2 diabetes.Keywords: TGR5, diabesity, atherogenic dyslipidemia, triglyceride clearance, remnant cholesterol, cardiovascular risksZambad SPTuli DMathur AGhalsasi SAChaudhary ARDeshpande SGupta RCChauthaiwale VDutt CDove Medical PressarticleSpecialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol 2014, Iss default, Pp 1-14 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Specialties of internal medicine RC581-951
spellingShingle	Specialties of internal medicine RC581-951 Zambad SP Tuli D Mathur A Ghalsasi SA Chaudhary AR Deshpande S Gupta RC Chauthaiwale V Dutt C TRC210258, a novel TGR5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity
description	Shitalkumar P Zambad, Davinder Tuli, Anoop Mathur, Sameer A Ghalsasi, Anita R Chaudhary, Shailesh Deshpande, Ramesh C Gupta, Vijay Chauthaiwale, Chaitanya DuttTorrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, IndiaBackground: Patients with diabesity have a significantly increased risk of developing cardiovascular disease. Therefore, therapy addressing the multiple metabolic abnormalities linked with diabesity and leading to further reduction of cardiovascular risk is highly desirable. Activation of the TGR5 receptor holds therapeutic potential for diabesity. In the present study, we evaluated the efficacy of TRC210258, a novel TGR5 agonist, in clinically relevant animal models of diabesity.Methods: A novel small molecule, TRC210258 (N-(4-chlorophenyl)-2-(4-fluoro phenoxy)-N-methylimidazo (1, 2-a) pyrimidine-3-carboxamide), was synthesized. The in vitro TGR5 receptor activation potential of TRC210258 was assessed by cyclic adinosine monophosphate (cAMP) assay and cAMP-responsive element reporter assay using cells overexpressing the human TGR5 receptor. The effect of TRC210258 on glucagon-like peptide-1 release was evaluated in vitro using a human enteroendocrine cell line. The effect of TRC210258 on energy expenditure and glycemic control was evaluated in high-fat diet-induced obese mice. Additionally, the effect of TRC210258 on dyslipidemic parameters was determined in high fat-fed hamsters.Results: TRC210258 demonstrated potent TGR5 agonist activity, with enhanced glucagon-like peptide-1 release and energy expenditure. Treatment with TRC210258 resulted in better glycemic control and improved parameters of dyslipidemia such as plasma triglyceride, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol levels. Treatment with TRC210258 also improved emerging dyslipidemic cardiovascular risk parameters, including remnant cholesterol and triglyceride clearance.Conclusion: This study highlights the potential of TRC210258, a novel TGR5 agonist, to improve dyslipidemic cardiovascular risk beyond glycemic control in patients with type 2 diabetes.Keywords: TGR5, diabesity, atherogenic dyslipidemia, triglyceride clearance, remnant cholesterol, cardiovascular risks
format	article
author	Zambad SP Tuli D Mathur A Ghalsasi SA Chaudhary AR Deshpande S Gupta RC Chauthaiwale V Dutt C
author_facet	Zambad SP Tuli D Mathur A Ghalsasi SA Chaudhary AR Deshpande S Gupta RC Chauthaiwale V Dutt C
author_sort	Zambad SP
title	TRC210258, a novel TGR5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity
title_short	TRC210258, a novel TGR5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity
title_full	TRC210258, a novel TGR5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity
title_fullStr	TRC210258, a novel TGR5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity
title_full_unstemmed	TRC210258, a novel TGR5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity
title_sort	trc210258, a novel tgr5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity
publisher	Dove Medical Press
publishDate	2013
url	https://doaj.org/article/0b3c46f8db6a4fa4898be37d7654f04c
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TRC210258, a novel TGR5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity

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