Design, synthesis and evaluation of 3-phenoxypyrazine-2-carboxamide derivatives as potent TGR5 agonists

Zhao, Shizhen; Wang, Le; Wang, Jie; Wang, Chenwei; Zheng, Shusen; Fu, Yajie; Li, Yunfu; Chen, Weidong; Hou, Ruifang; Yang, Dongbin; Wang, Yandong

doi:10.1039/d1ra08867j

Search citation statements

Order By: Relevance

Paper Sections

Select...

Natural and Synthetic Ligands Of Tgr51

Citation Types

Supporting

Mentioning

Contrasting

Year Published

2024

Publication Types

Select...

Article2

Relationship

Self Cite0

Independent2

Authors

Journals

Cited by 2 publications

(1 citation statement)

References 23 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 66 synthesized ligand compound 4b with strong TGR5 agonist activity by using TMN (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene) as the skeleton, which provides a potential drug choice for the treatment of dyslipidaemia. In addition, TGR5 agonists in the past 5 years are listed in Table 1 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 .…”

Section: Natural and Synthetic Ligands Of Tgr5mentioning

confidence: 99%

Mechanism of action of the bile acid receptor TGR5 in obesity

Lun,

Yan,

Guo

et al. 2024

Acta Pharmaceutica Sinica B

View full text Add to dashboard Cite

Section: Natural and Synthetic Ligands Of Tgr5mentioning

confidence: 99%

Mechanism of action of the bile acid receptor TGR5 in obesity

Lun,

Yan,

Guo

et al. 2024

Acta Pharmaceutica Sinica B

View full text Add to dashboard Cite

Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

Fleishman,

Kumar

2024

Sig Transduct Target Ther

View full text Add to dashboard Cite

Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.

show abstract

Design, synthesis and evaluation of 3-phenoxypyrazine-2-carboxamide derivatives as potent TGR5 agonists

Abstract: The most potent compound 18k exhibited excellent hTGR5 agonist activity, which was superior to those of the reference drugs INT-777. In addition, compound 18k could significantly reduce blood glucose levels and stimulate GLP-1 secretion in C57 BL/6 mice.

Cited by 2 publications

References 23 publications

Mechanism of action of the bile acid receptor TGR5 in obesity

Mechanism of action of the bile acid receptor TGR5 in obesity

Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

Contact Info

Product

Resources

About