Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists

Miyata, Sachiho; Kawashima, Yuji; Sakai, Miku; Matsubayashi, Masaya; Motoki, Keisuke; Miyajima, Yui; Watanabe, Yousuke; Chikamatsu, Noriko; Taniguchi, Tetsuya; Tokuyama, Ryukou

doi:10.1038/s41598-021-88493-0

Cited by 13 publications

(7 citation statements)

References 48 publications

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“…Interesting perspectives derive from experimental studies using FXR-TGR5 dual agonists [ 25 , 265 , 266 ]. Recently, in a mouse model of NASH, treatment with the FXR-TGR5 dual agonist INT-767 was able to prevent the progression of disease, with beneficial effects on liver mitochondrial function, lipid homeostasis, BA composition (i.e., decreased hydrophobicity index), liver inflammation and gut dysbiosis [ 25 ].…”

Section: Fxr As a Therapeutic Target?mentioning

confidence: 99%

Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling

et al. 2022

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Bile acids (BA) are amphiphilic molecules synthesized in the liver (primary BA) starting from cholesterol. In the small intestine, BA act as strong detergents for emulsification, solubilization and absorption of dietary fat, cholesterol, and lipid-soluble vitamins. Primary BA escaping the active ileal re-absorption undergo the microbiota-dependent biotransformation to secondary BA in the colon, and passive diffusion into the portal vein towards the liver. BA also act as signaling molecules able to play a systemic role in a variety of metabolic functions, mainly through the activation of nuclear and membrane-associated receptors in the intestine, gallbladder, and liver. BA homeostasis is tightly controlled by a complex interplay with the nuclear receptor farnesoid X receptor (FXR), the enterokine hormone fibroblast growth factor 15 (FGF15) or the human ortholog FGF19 (FGF19). Circulating FGF19 to the FGFR4/β-Klotho receptor causes smooth muscle relaxation and refilling of the gallbladder. In the liver the binding activates the FXR-small heterodimer partner (SHP) pathway. This step suppresses the unnecessary BA synthesis and promotes the continuous enterohepatic circulation of BAs. Besides BA homeostasis, the BA-FXR-FGF19 axis governs several metabolic processes, hepatic protein, and glycogen synthesis, without inducing lipogenesis. These pathways can be disrupted in cholestasis, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Thus, targeting FXR activity can represent a novel therapeutic approach for the prevention and the treatment of liver and metabolic diseases.

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Section: Fxr As a Therapeutic Target?mentioning

confidence: 99%

Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling

et al. 2022

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“…Recently, Tokuyama et al developed the first non-bile acid FXR/TGR5 dual agonists through developing chimera compounds between potent FXR agonist 85 and TGR5 agonist 86 (Figure 27). 139 To explore the SAR of rings C and D, several substituted and unsubstituted pyridines and phenyl ringS were used in lieu of the cyclohexyl group, and various mono-and disubstituted aniline analogs were introduced to replace the central aniline ring (ring D). The 2-methyl isonicotinamide group that was important for TGR5 agonist activity showed the best dual agonistic activity toward both receptors, and the positions of the methyl group and the pyridine nitrogen were crucial to maintain such activity.…”

Section: Fxr Antagonistsmentioning

confidence: 99%

Recent Advances in the Medicinal Chemistry of Farnesoid X Receptor

et al. 2021

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Farnesoid X receptor (FXR) is an important regulator of bile acid, lipid, amino acid, and glucose homeostasis, hepatic inflammation, regeneration, and fibrosis. FXR has been recognized as a promising drug target for various metabolic diseases such as lipid disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and chronic kidney disease. A large number of FXR ligands have been developed by pharmaceutical companies and academic institutions, and several candidates have progressed into clinical trials in the past decade. However, it is continually a challenge to discover drugs targeting FXR due to side effects associated with long-term administration. In this perspective, we summarize the research progress on medicinal chemistry of FXR modulators from 2018 to the present by discussing the diverse structures of synthetic FXR modulators including steroidal and non-steroidal ligands, their structure–activity relationships (SARs), and their therapeutic applications.

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“…More recently, there is an interest in developing FXR/TGR5 dual agonists due to an eventual synergistic effect [ 169 ]. Some beneficial effects have been reported in preclinical studies of kidney disease and liver steatosis through anti-inflammatory mechanisms [ 170 – 173 ].…”

Section: Clinical Perspective and Conclusionmentioning

confidence: 99%

Redox‐Dependent Effects in the Physiopathological Role of Bile Acids

Orozco-Aguilar

Simón

Cabello-Verrugio

2021

Oxidative Medicine and Cellular Longevity

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Bile acids (BA) are recognized by their role in nutrient absorption. However, there is growing evidence that BA also have endocrine and metabolic functions. Besides, the steroidal-derived structure gives BA a toxic potential over the biological membrane. Thus, cholestatic disorders, characterized by elevated BA on the liver and serum, are a significant cause of liver transplant and extrahepatic complications, such as skeletal muscle, central nervous system (CNS), heart, and placenta. Further, the BA have an essential role in cellular damage, mediating processes such as membrane disruption, mitochondrial dysfunction, and the generation of reactive oxygen species (ROS) and oxidative stress. The purpose of this review is to describe the BA and their role on hepatic and extrahepatic complications in cholestatic diseases, focusing on the association between BA and the generation of oxidative stress that mediates tissue damage.

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Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists

Cited by 13 publications

References 48 publications

Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling

Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling

Recent Advances in the Medicinal Chemistry of Farnesoid X Receptor

Redox‐Dependent Effects in the Physiopathological Role of Bile Acids

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