title: TRC210258, a novel TGR5 agonist, reduces glycemic and dyslipidemic cardiovascular risk in animal models of diabesity.
abstract: BACKGROUND
  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-fluorophenoxy)-N-methylimidazo (1, 2-a) pyrimidine-3-carboxamide), was synthesized. The in vitro TGR5 receptor activation potential of TRC210258 was assessed by cyclic adenosine 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, India.
authors.forename: Shitalkumar P
authors.initials: SP
authors.lastname: Zambad
authors.affiliation: Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, India.
authors.forename: Davinder
authors.initials: D
authors.lastname: Tuli
authors.affiliation: Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, India.
authors.forename: Anoop
authors.initials: A
authors.lastname: Mathur
authors.affiliation: Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, India.
authors.forename: Sameer A
authors.initials: SA
authors.lastname: Ghalsasi
authors.affiliation: Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, India.
authors.forename: Anita R
authors.initials: AR
authors.lastname: Chaudhary
authors.affiliation: Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, India.
authors.forename: Shailesh
authors.initials: S
authors.lastname: Deshpande
authors.affiliation: Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, India.
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Gupta
authors.affiliation: Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Chauthaiwale
authors.affiliation: Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gujarat, India.
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Dutt
keywords: TGR5; atherogenic dyslipidemia; cardiovascular risks; diabesity; remnant cholesterol; triglyceride clearance