Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists

Duan, Hongliang; Ning, Man; Chen, Xiaoyan; Zou, Qingan; Zhang, Liming; Feng, Ying; Zhang, Lina; Liu, Ying; Shen, Jianhua

doi:10.1021/jm301071h

Cited by 71 publications

(67 citation statements)

References 26 publications

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“…Activation of TGR5 in other tissues, however, can lead to undesired side effects. In the gallbladder, TGR5 activation causes smooth muscle relaxation and promotes gallbladder filling [24,25] . Gallbladder toxicity has been reported for many TGR5 agonists due to high exposure to bile.…”

Section: Resultsmentioning

confidence: 99%

Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy

Wang

Zhang

et al. 2014

Acta Pharmacol Sin

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Aim: TGR5 is a G protein-coupled receptor that is expressed in intestinal L-cells and stimulates glucagon-like peptide 1 (GLP-1) secretion. TGR5 may represent a novel target for the treatment of metabolic disorder. Here, we sought to design and synthesize a series of TGR5 agonists derived from the natural product betulinic acid. Methods: A series of betulinic acid derivatives were designed and synthesized. A cAMP assay was established using a HEK293 cell line expressing human TGR5. Luciferase reporter assay was established using HEK293 cells transfected with plasmids encoding human FXR and luciferase reporter. A human intestinal L-cell line NCI-H716 was used to evaluate the effects of the betulinic acid derivatives on GLP-1 secretion in vitro. Results: Biological data revealed that the 3-α-OH triterpenoids consistently show increased potency for TGR5 compared to their 3-β-OH epimers. 3-OH esterification increased the lipophilicity and TGR5 activity of 3-α betulinic derivatives and enhanced the activity differences between 3-α and 3-β derivatives. The 3-α-acyloxy betulinic acids also exhibited a significant dose-dependent GLP-1 secretion effect. Conclusion: This study demonstrates that highly lipophilic 3-epi-betulinic acid derivatives can be potent and selective TGR5 agonists with improved cellular efficacy, and our research here provides a new strategy for the design and development of potent TGR5 agonists.

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Section: Resultsmentioning

confidence: 99%

Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy

Wang

Zhang

et al. 2014

Acta Pharmacol Sin

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“…22) Using this scaffold as a basis, most of our previous structural explorations were focused on the upper tetrahydroquinoxaline region and the bottom phenyl ring, 22,24) whereas few explorations were carried out at the central core part, which was previously thought of as a limited region to alter. For this work, we investigated whether these alterations at the central core part would generate additional potent TGR5 agonists for further studies.…”

Section: )mentioning

confidence: 99%

“…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 compound (SB-756050) has ever been advanced into the clinical trial phase, and most are still in the discovery phase, because of a lack of appropriate Pharmacokinetic/Pharmacodynamic (PK/PD) profiles, or having side effects such as stimulating filling of the gallbladder, 22,23) or causing changes in heart rate and blood pressure.18) Therefore, the search for a greater variety of promising TGR5 agonists with potent in vitro activity to expand the chemical library of TGR5 agonists still represents a very urgent need, and further optimizations based on such agonists could increase the possibility of producing drug candidates with good in vivo potency and low side-effects.In our initial efforts to find novel TGR5 agonists, a scaffold of 4-phenoxynicotinamide (Fig. 2, scaffold A) was developed.…”

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confidence: 99%

“…[15][16][17][18][19][20][21][22] However, only one compound (SB-756050) has ever been advanced into the clinical trial phase, and most are still in the discovery phase, because of a lack of appropriate Pharmacokinetic/Pharmacodynamic (PK/PD) profiles, or having side effects such as stimulating filling of the gallbladder, 22,23) or causing changes in heart rate and blood pressure.…”

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confidence: 99%

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

Chen

Ning

Zou

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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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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“…For example, observed increases in bile flow and plasma bile acids associated with the immediate post-RYGB period and believed to stimulate b-cell function by potentiating incretin-hormone (i.e., GLP-1) signaling via activation of the G-protein-coupled bile acid receptor (TGR5) have prompted discovery campaigns to design proprietary, orally active TGR5 agonists as antidiabetic agents [71,72]. Likewise, the critical role of the high-affinity sodium-glucose cotransporter (SGLT-1) in both glucose transport by the proximal intestine and consequent nutrientsensing information pathways, the SGLT-1 overexpression observed in experimental and clinical T2D, and the reduced glucose-transport capacity of the proximal intestine following RYGB have led to the development of novel SGLT-1 inhibitors with preclinical antidiabetic efficacy [73][74][75].…”

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confidence: 99%

Synthetic agents in the context of metabolic/bariatric surgery: expanding the scope and impact of diabetes drug discovery

Janero

2014

Expert Opinion on Drug Discovery

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Type 2 diabetes (T2D) --particularly with concurrent obesity ('diabesity') --is an intensifying global public-health problem. Medical needs and market opportunities in the T2D space have propelled discovery efforts aimed at inventing new synthetic T2D drugs differentiable by improved safety and efficacy and/ or the ability to modulate emerging T2D targets. Particularly for moderately and severely obese individuals, weight-loss (bariatric) surgery offers an effective means of reducing obesity-driven T2D that is superior in many respects to medical T2D management. Yet, not all overweight or obese individuals with T2D qualify for bariatric surgery, and current healthcare resources are inadequate for applying surgical T2D control to more than a very small segment of qualified patients. Bariatric surgery is no guarantee of 'curative' T2D abrogation, significant rates of T2D non-remission or re-emergence having been observed in diabesity patients following bariatric procedures. Preoperative glucose control by oral hypoglycemic drugs reduces the chance of T2D recurrence post-surgery, and diabesity patients in whom glycemic indices have been improved by bariatric surgery may still require some level of T2D pharmacotherapy. Laboratory and clinical data indicate that synthetic T2D drugs can improve T2D-related outcomes following bariatric procedures, and current T2D drug-discovery efforts are being informed by the metabolic advantages associated with bariatric surgery. These circumstances intensify the need for and extend the impact of T2D drug discovery by demonstrating multiple levels of interplay between medical and surgical approaches to improve the health of individuals with diabesity and, perhaps, approach the overarching goal of decreasing long-term cardiovascular mortality.Keywords: cardiovascular risk, diabesity, endocrine disease, glycemic control, insulin resistance, metabolic syndrome, obesity, vascular disease Expert Opin. Drug Discov. (2014) 9(3):221-228 BackgroundIn the November, 2013, issue of Expert Opinion on Drug Discovery, Safavi et al. [1] surveyed approved synthetic drugs and late-stage pipeline compounds as pharmacotherapeutics for type 2 diabetes (T2D). Concluding that 'finding new targets and ... synthetic methods' is the 'main goal in T2D drug discovery,' the authors mention in passing that weight-loss (bariatric) surgery 'is a highly effective treatment for obesity-related T2D.' This commentary aims to widen the aperture afforded by Safavi and colleagues by considering the proposition that the inability of bariatric surgery to eradicate the T2D pandemic expands the scope of and presents new opportunities for drug discovery in the T2D space. 221All rights reserved: reproduction in whole or in part not permitted 2. Bariatric surgery can effectively address, but has not solved, the T2D problemAn intensifying worldwide epidemic, obesity contributes to the development of numerous disabling and lifespan-limiting maladies. One of these, T2D, is well recognized as obesity's principal metabolic comorb...

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Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists

Cited by 71 publications

References 26 publications

Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy

Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy

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

Synthetic agents in the context of metabolic/bariatric surgery: expanding the scope and impact of diabetes drug discovery

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