Discovery of a Potent and Orally Efficacious TGR5 Receptor Agonist

Agarwal, Sameer; Patil, Amit B; Aware, Umesh; Deshmukh, Prashant; Darji, Brijesh; Sasane, Santosh; Sairam, Kalapatapu V.V.M.; Priyadarsiny, Priyanka; Giri, Poonam; Patel, Harilal; Giri, Suresh; Jain, Mukul; Desai, Ranjit C.

doi:10.1021/acsmedchemlett.5b00323

Cited by 32 publications

(24 citation statements)

References 29 publications

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“…In the new reports, Kumar et al (2016) shown that TGR5 induced GLP-1 release from pancreatic α cells via an Epac-mediated PKA-independent mechanism. Agarwal et al (2016) also shown the important roles of TGR5 in T2D. All of these studies indicate the important functions of TGR5 in T2D treatment.…”

Section: Tgr5 and Different Diseasesmentioning

confidence: 80%

TGR5, Not Only a Metabolic Regulator

2016

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G-protein-coupled bile acid receptor, Gpbar1 (TGR5), is a member of G-protein-coupled receptor (GPCR) superfamily. High levels of TGR5 mRNA were detected in several tissues such as small intestine, stomach, liver, lung, especially in placenta and spleen. TGR5 is not only the receptor for bile acids, but also the receptor for multiple selective synthetic agonists such as 6α-ethyl-23(S)-methyl-cholic acid (6-EMCA, INT-777) and a series of 4-benzofuranyloxynicotinamde derivatives to regulate different signaling pathways such as nuclear factor κB (NF-κB), AKT, and extracellular signal-regulated kinases (ERK). TGR5, as a metabolic regulator, is involved in energy homeostasis, bile acid homeostasis, as well as glucose metabolism. More recently, our group and others have extended the functions of TGR5 to more than metabolic regulation, which include inflammatory response, cancer and liver regeneration. These findings highlight TGR5 as a potential drug target for different diseases. This review summarizes the basic information of TGR5 and its new functions.

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Section: Tgr5 and Different Diseasesmentioning

confidence: 80%

TGR5, Not Only a Metabolic Regulator

2016

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“…Another proposed mechanism by which bile acids may impact hepatocellular energy metabolism is via activation of the G-protein coupled receptor TGR5 which in turn increase deiodinase-2 expression and activation of thyroid hormone. Some TGR5 agonists have been reported to have glucose lowering (Agarwal et al, 2016; Briere et al, 2015) and lipid-lowering (Zambad et al, 2013) effects in rodents, but the effects on NAFLD have not been reported. TGR5 activation promotes gallbladder filling and thus agonists against TGR5 have the potential to promote gallstone formation.…”

Section: Peroxisome Proliferator-activated Receptor Agonists (Ppar’s)mentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases

2018

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NAFLD is closely linked with hepatic insulin resistance. Accumulation of hepatic diacylglycerol activates PKC-ε, impairing insulin receptor activation and insulin-stimulated glycogen synthesis. Peripheral insulin resistance indirectly influences hepatic glucose and lipid metabolism by increasing flux of substrates that promote lipogenesis (glucose and fatty acids) and gluconeogenesis (glycerol and fatty acid-derived acetyl-CoA, an allosteric activator of pyruvate carboxylase). Weight loss with diet or bariatric surgery effectively treats NAFLD, but drugs specifically approved for NAFLD are not available. Some new pharmacological strategies act broadly to alter energy balance or influence pathways that contribute to NAFLD (e.g., agonists for PPAR γ, PPAR α/δ, FXR and analogs for FGF-21, and GLP-1). Others specifically inhibit key enzymes involved in lipid synthesis (e.g., mitochondrial pyruvate carrier, acetyl-CoA carboxylase, stearoyl-CoA desaturase, and monoacyl- and diacyl-glycerol transferases). Finally, a novel class of liver-targeted mitochondrial uncoupling agents increases hepatocellular energy expenditure, reversing the metabolic and hepatic complications of NAFLD.

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“…Therefore, TGR5 activation provides a promising strategy for treatment of type 2 diabetes mellitus and associated metabolic disorders 10 11 12 . Thus TGR5 has drawn considerable attention from both academia and industry 13 14 15 16 17 18 .…”

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confidence: 99%

Intestinally-targeted TGR5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect

Cao

Chen

Wang

et al. 2016

Sci Rep

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TGR5 activation of enteroendocrine cells increases glucagon-like peptide 1 (GLP-1) release, which maintains glycemic homeostasis. However, TGR5 activation in the gallbladder and heart is associated with severe side effects. Therefore, intestinally-targeted TGR5 agonists were suggested as potential hypoglycemic agents with minimal side effects. However, until now no such compounds with robust glucose-lowering effects were reported, especially in diabetic animal models. Herein, we identify a TGR5 agonist, 26a, which was proven to be intestinally-targeted through pharmacokinetic studies. 26a was used as a tool drug to verify the intestinally-targeted strategy. 26a displayed a robust and long-lasting hypoglycemic effect in ob/ob mice (once a day dosing (QD) and 18-day treatment) owing to sustained stimulation of GLP-1 secretion, which suggested that robust hypoglycemic effect could be achieved with activation of TGR5 in intestine alone. However, the gallbladder filling effect of 26a was rather complicated. Although the gallbladder filling effect of 26a was decreased in mice after once a day dosing, this side effect was still not eliminated. To solve the problem above, several research strategies were raised for further optimization.

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Discovery of a Potent and Orally Efficacious TGR5 Receptor Agonist

Cited by 32 publications

References 29 publications

TGR5, Not Only a Metabolic Regulator

TGR5, Not Only a Metabolic Regulator

Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases

Intestinally-targeted TGR5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect

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