Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes

Duan, Hongliang; Ning, Man; Zou, Qingan; Ye, Yangliang; Feng, Ying; Zhang, Lina; Liu, Ying; Shen, Jianhua

doi:10.1021/jm500829b

Cited by 79 publications

(61 citation statements)

References 33 publications

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“…MN6 demonstrated a high permeability in Caco-2 cells in our previous report (P app =6.75×10 -6 cm/s) [20] . In the current study, Caco-2 cells were used to evaluate the permeability of OL3 in vitro.…”

Section: Ol3 Demonstrated Low Permeability In Caco-2 Cellssupporting

confidence: 48%

“…Among them, MN6 ([4-(2, 5-dichlorophenoxy) pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-l-yl) methanone (described as compound 22g in reference 19) is one of the most potent molecules with an EC 50 of 1.5 nmol/L and 18 nmol/L on human and mouse TGR5 (h/mTGR5), respectively, and without activation effects on FXR [19] . Oral administration of MN6 (described as compound 2 in reference 20) also increased the gallbladder volume in mice [20] . Compounds with a large molecular weight (MW) and a high topological polar surface area (tPSA) exhibit low membrane permeability and decreased intestinal absorption [21] .…”

Section: Original Articlementioning

confidence: 97%

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OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition

Ning

Zou

et al. 2016

Acta Pharmacol Sin

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Aim: TGR5 agonists stimulate intestinal glucagon-like peptide-1 (GLP-1) release, but systemic exposure causes unwanted side effects, such as gallbladder filling. In the present study, linagliptin, a DPP-4 inhibitor with a large molecular weight and polarity, and MN6, a previously described TGR5 agonist, were linked to produce OL3, a novel low-absorbed TGR5 agonist with reduced side-effects and dual function in lowering blood glucose by activation of TGR5 and inhibition of DPP-4. Methods: TGR5 activation was assayed in HEK293 cells stably expressing human or mouse TGR5 and a CRE-driven luciferase gene. DPP-4 inhibition was assessed based on the rate of hydrolysis of a surrogate substrate. GLP-1 secretion was measured in human enteroendocrine NCI-H716 cells. OL3 permeability was tested in Caco-2 cells. Acute glucose-lowering effects of OL3 were evaluated in ICR and diabetic ob/ob mice. Results: OL3 activated human and mouse TGR5 with an EC 50 of 86.24 and 17.36 nmol/L, respectively, and stimulated GLP-1 secretion in human enteroendocrine NCI-H716 cells (3-30 μmol/L). OL3 inhibited human and mouse DPP-4 with IC 50 values of 18.44 and 69.98 μmol/L, respectively. Low permeability of OL3 was observed in Caco-2 cells. In ICR mice treated orally with OL3 (150 mg/kg), the serum OL3 concentration was 101.10 ng/mL at 1 h, and decreased to 13.38 ng/mL at 5.5 h post dose, confirming the low absorption of OL3 in vivo. In ICR mice and ob/ob mice, oral administration of OL3 significantly lowered the blood glucose levels, which was a synergic effect of activating TGR5 that stimulated GLP-1 secretion in the intestine and inhibiting DPP-4 that cleaved GLP-1 in the plasma. In ICR mice, oral administration of OL3 did not cause gallbladder filling. Conclusion: OL3 is a low-absorbed TGR5 agonist that lowers blood glucose without inducing gallbladder filling. This study presents a new strategy in the development of potent TGR5 agonists in treating type 2 diabetes, which target to the intestine to avoid systemic side effects.

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Section: Ol3 Demonstrated Low Permeability In Caco-2 Cellssupporting

confidence: 48%

Section: Original Articlementioning

confidence: 97%

OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition

Ning

Zou

et al. 2016

Acta Pharmacol Sin

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“…It could be noted that various substitutions at position 4 of compound 30c were well tolerated, such as bromo (30n), methyl (31c) and hydroxyl (31d) substituents, which suggested that other groups might also be well tolerated. 32) As a general rule, the 2-methylthiazole scaffold successfully maintained excellent in vitro potency.…”

Section: Resultsmentioning

confidence: 93%

Discovery and Structure–Activity Relationship Study of 4-Phenoxythiazol-5-carboxamides as Highly Potent TGR5 Agonists

et al. 2016

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A novel therapy that stimulates endogenous glucagon-like peptide-1 (GLP-1) secretion by Takeda G-protein-coupled receptor 5 (TGR5) agonists might be a superior alternative for the treatment of type 2 diabetes mellitus. A series of 4-phenoxythiazol-5-carboxamides were developed as highly potent TGR5 agonists using a bioisosteric replacement strategy based on the scaffold of 4-phenoxynicotinamides. The structure-activity relationship on the bottom phenyl ring and the thiazole ring was extensively studied, and the 2-methylthiazole derivatives 30c and e displayed the best in vitro potency toward human TGR5, with EC 50 values of approximately 1 nM. While endowed with excellent in vitro potency, the 2-methyl-thiazoles were flawed with high microsomal clearance.Key words Takeda G-protein-coupled receptor 5 agonist; bioisostere; microsomal clearance; structureactivity relationship Takeda G-protein-coupled receptor 5 (TGR5), also known as G-protein coupled bile acid receptor 1 (GPBAR1), is a cell surface receptor responsive to bile acids. It has been found to be ubiquitously expressed in animal and human tissues, including the liver, intestine, heart, spleen, skeletal muscle, brown adipose tissue, gallbladder and brain. [1][2][3][4] It is thought to play an important role in the regulation of energy homeostasis and glucose metabolism. Activation of the TGR5 receptor by bile acids triggers an increase in energy expenditure in brown adipose tissue and skeletal muscle.5) More importantly, TGR5 activation also promotes glucagon-like peptide-1 (GLP-1) secretion in the intestine. 6) As a member of the incretin family, GLP-1 acts as an important physiological regulator in glucose control via several mechanisms of action.7) But endogenous GLP-1 is significantly limited as a direct drug for the treatment of type 2 diabetes because of its rapid inactivation in plasma by dipeptidyl peptidase-4 (DPP-4). There are two main classes of alternative GLP-1-based drugs being widely used in a clinical setting: DPP-4 inhibitors and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists. 8) However, these drugs may not be able to halt the progression of type 2 diabetes because they all exert their actions through increasing the plasma concentration of "GLP-1R agonists," and they thus may lack some of the local actions that endogenous GLP-1 is likely to have. 9)Therefore, a novel therapy that stimulates endogenous GLP-1 secretion by TGR5 agonists is considered as a superior alternative for the treatment of type 2 diabetes mellitus.In recent years, many different kinds of TGR5 agonists have been reported (Fig. 1). Structurally, TGR5 agonists can fall into two categories. The first category is bile acid derivatives, [10][11][12] such as lithocholic acid (LCA) and 6α-ethyl-23(S)-methylcholic acid (INT-777). The second category is non-bile acid derivatives, including naturally occurring non-bile acid agonists such as oleanolic acid and betulinic acid, 13,14) and synthetic small molecular TGR5 agonists. [15][16][17][18][19][20][21][22] However, only one ...

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“…Therefore, TGR5 has emerged as an attractive drug target for metabolic diseases and various TGR5 agonists have been developed [5,23,24,[36][37][38][39][40] .…”

Section: Tgr5 In Liver Damage: Insights From Mice Treated With Varioumentioning

confidence: 99%

“…Furthermore, due to the extremely high expression of TGR5 in gallbladder tissue as compared to other tissues such as the intestine, effects on gallbladder filling were observed with lower concentrations of a TGR5 agonist (compound 18) as effects on GLP-1 secretion [5] . These findings may limit the use of systemically available TGR5 agonists for the treatment of metabolic disease, however, may be overcome by molecules with low systemic bioavailability, which specifically target intestinal TGR5 [5,36] .…”

Section: Tgr5 In Liver Damage: Insights From Mice Treated With Varioumentioning

confidence: 99%

Role of the G Protein-Coupled Bile Acid Receptor TGR5 in Liver Damage

Reich

Klindt²,

Deutschmann³

et al. 2017

Dig Dis

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Background: TGR5 (G protein-coupled bile acid receptor 1, M-Bar) is a G protein-coupled cell surface receptor responsive to bile acids (BA) and different steroid hormones. TGR5 mRNA is detected almost ubiquitious in human and rodent tissues with a very high expression in gallbladder, liver and intestine. In liver, TGR5 is found in sinusoidal endothelial cells, Kupffer cells and cholangiocytes. Activation of TGR5 triggers an elevation of intracellular cyclic AMP and further downstream signalling. Key Messages: TGR5 exerts anti-inflammatory effects, protects cholangiocytes from BA-induced toxicity, promotes cholangiocyte secretion and proliferation and reduces portal perfusion pressure. Furthermore, TGR5 mediates gallbladder filling. TGR5 knockout mice have a smaller BA pool size with altered composition and develop more severe liver injury after BA feeding, common bile duct ligation or injection of lipopolysaccharide. The absence of TGR5 also reduces the proliferative and regenerative capacity after partial hepatectomy or liver damage. Stimulation of TGR5 signalling can improve steatohepatitis, portal hypertension and hepatic inflammation in rodent models of liver damage. However, TGR5 activation also promotes the proliferation of cystic and malignant-transformed cholangiocytes. Conclusions: TGR5 plays an important role in the protection of the liver from BA toxicity under cholestatic conditions. Stimulation of the receptor prevents excessive liver damage in rodent models of cholestasis, steatohepatitis, liver fibrosis and inflammation and also promotes liver regeneration. However, the activation of TGR5-dependent signalling may also trigger proliferation and apoptosis resistance of cystic cholangiocytes and malignantly transformed cholangiocytes, thus promoting cyst growth in polycystic liver disease or progression of cholangiocarcinoma. Depending on the type of liver disease stimulation as well as inhibition of TGR5, signalling may present a useful therapeutic approach.

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Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes

Cited by 79 publications

References 33 publications

OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition

OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition

Discovery and Structure–Activity Relationship Study of 4-Phenoxythiazol-5-carboxamides as Highly Potent TGR5 Agonists

Role of the G Protein-Coupled Bile Acid Receptor TGR5 in Liver Damage

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