Discovery of Trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as Potent, Orally Bioavailable TGR5 (GPBAR1) Agonists: Structure–Activity Relationships, Lead Optimization, and Chronic In Vivo Efficacy

Phillips, Dean; Gao, Wenqi; Yang, Yang; Zhang, Guobao; Lerario, Isabelle K.; Lau, Thomas L.; Jiang, Jiaoyang; Wang, Xia; Nguyen, Deborah G.; Bhat, Balkrishen; Trotter, Carol; Sullivan, Heather J.; Welzel, Gustav; Landry, Jannine; Chen, Yali; Joseph, Sean B.; Li, Chun; Gordon, W. Perry; Richmond, Wendy; Johnson, Kevin C.; Bretz, Angela; Bursulaya, Badry; Pan, Shifeng; McNamara, Peter; Seidel, H. Martin

doi:10.1021/jm401731q

Cited by 38 publications

(29 citation statements)

References 38 publications

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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%

“…1 ) causes smooth-muscle relaxation, prevents bile secretion, and greatly increases gallbladder volume 14 19 20 . Several absorbed TGR5 agonists have been shown to change heart rate and blood pressure in dogs 15 21 22 . Therefore, it was suggested that localized activation of TGR5 within the intestinal tract while avoiding systemic exposure (i. e. intestinally-targeted) could be a promising anti-diabetes mellitus strategy with minimal side effects 23 24 .…”

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confidence: 99%

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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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confidence: 99%

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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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“…Therefore, the no-observed, adverse-effect level of RDX8940 in the 7-day dose-range-finding study was determined to be 300 mg·kg −1 ·day −1 , which produced no significant effects on organ weights or histological findings. Pathologies of known TGR5 agonists (19, 28, 29), seen in preclinical animal studies, including cardiac, hepatic, and pancreatic toxicities, were not observed.…”

Section: Resultsmentioning

confidence: 94%

“…TGR5 agonists may have therapeutically beneficial effects in patients with NAFLD/NASH via stimulation of GLP-1 and GLP-2 production (31, 35). However, clinical development of TGR5 agonists for the treatment of metabolic diseases has been hindered by side effects associated with systemic TGR5 agonism, including inhibition of gallbladder emptying (5, 22), which can lead to gallstone formation, and changes in heart rate and blood pressure (28, 29). Therapeutically targeting intestinal TGR5 with molecules that are not systemically absorbed could potentially avoid these unwanted side effects by preventing activation of TGR5 receptors expressed in tissues elsewhere in the body, such as the gallbladder.…”

Section: Introductionmentioning

confidence: 99%

Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice

Finn

Rodríguez

Kohler

et al. 2019

American Journal of Physiology-Gastrointestinal and Liver Physi

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Takeda G protein-coupled receptor 5 (TGR5) agonists induce systemic release of glucagon-like peptides (GLPs) from intestinal L cells, a potentially therapeutic action against metabolic diseases such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and Type 2 diabetes. Historically, TGR5 agonist use has been hindered by side effects, including inhibition of gallbladder emptying. Here, we characterize RDX8940, a novel, orally administered TGR5 agonist designed to have minimal systemic effects and investigate its activity in mice fed a Western diet, a model of NAFLD and mild insulin resistance. Agonist activity, binding selectivity, toxicity, solubility, and permeability of RDX8940 were characterized in standard in vitro models. RDX8940 pharmacokinetics and effects on GLP secretion, insulin sensitivity, and liver steatosis were assessed in C57BL/6 mice fed normal or Western diet chow and given single or repeated doses of RDX8940 or vehicle, with or without dipeptidyl peptidase-4 (DPP4) inhibitors. Gallbladder effects were assessed in CD-1 mice fed normal chow and given RDX8940 or a systemic TGR5 agonist or vehicle. Our results showed that RDX8940 is minimally systemic, potent, and selective, and induces incretin (GLP-1, GLP-2, and peptide YY) secretion. RDX8940-induced increases in plasma active GLP-1 (aGLP-1) levels were enhanced by repeated dosing and by coadministration of DPP4 inhibitors. RDX8940 increased hepatic exposure to aGLP-1 without requiring coadministration of a DPP4 inhibitor. In mice fed a Western diet, RDX8940 improved liver steatosis and insulin sensitivity. Unlike systemic TGR5 agonists, RDX8940 did not inhibit gallbladder emptying. These results indicate that RDX8940 may have therapeutic potential in patients with NAFLD/NASH. NEW & NOTEWORTHY Takeda G protein-coupled receptor 5 (TGR5) agonists have potential as a treatment for nonalcoholic steatohepatitis and nonalcoholic fatty liver disease (NAFLD) but have until now been associated with undesirable side effects associated with systemic TGR5 agonism, including blockade of gallbladder emptying. We demonstrate that RDX8940, a potent, selective, minimally systemic oral TGR5 agonist, improves liver steatosis and insulin sensitivity in a mouse model of NAFLD and does not inhibit gallbladder emptying in mice.

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“…Evidence: effect of ASO in DIO mice [179] TGR5 receptor: its activation leads to secretion of GLP-1 and other related incretins in gut enteroendocrine cells and to a decrease in LPS Th1 cytokines like TNF-α and IL-12 in monocytes/macrophages and dendritic cells. Evidence: low MW compounds activity in ob/ob mice (target: Type 2 diabetes) [180] Agonists to hNMU receptors. Evidence: KO mouse.…”

Section: Targetmentioning

confidence: 99%

New Perspectives on the Development of Antiobesity Drugs

Costantino

Barlocco

2015

Future Med. Chem.

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After many years of research, obesity is still a disease with an unmet medical need. Very few compounds have been approved, acting mainly on neuromediators; researches, in recent years, pointed toward compounds potentially safer than first-generation antiobesity drugs, able to interact with one or more (multitarget therapy) receptors for substances produced by the gut, adipose tissue and other targets outside CNS. Other holistic approaches, such as those involving gut microbiota and plant extracts, appeared recently in the literature, and undoubtedly will contribute to the discovery of a valuable therapy for this disease. This review deals with the positive results and the pitfalls obtained following these approaches, with a view on their clinical trial studies.

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Discovery of Trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as Potent, Orally Bioavailable TGR5 (GPBAR1) Agonists: Structure–Activity Relationships, Lead Optimization, and Chronic In Vivo Efficacy

Cited by 38 publications

References 38 publications

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

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

Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice

New Perspectives on the Development of Antiobesity Drugs

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