Synthesis and Biological Evaluation of a Series of Bile Acid Derivatives as FXR Agonists for Treatment of NASH

Xiao, Hualing; Li, Xin; He, Haiying; Wang, Jianhua; Guo, Fengxun; Zhang, Jiliang; Lu-xia, Wei; Zhang, Hongmei; Shi, Yueyuan; Hou, Lijuan; Shen, Liang; Chen, Zhenxia; Du, Chunfang; Fu, Shouliang; Zhang, Pengtao; Hao, Fei; Wang, Ping; Xu, Deming; Liang, Wei; Tian, Xin; Zhang, Aiming; Cheng, X.; Yang, Ling; Wang, Xiangjian; Zhang, Xiquan; Li, Jian; Chen, Shuhui

doi:10.1021/acsmedchemlett.7b00318

Cited by 18 publications

(6 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This result is consistent with the results of a recent study which found that replacing the acid moiety of obeticholic acid with a tetrazole also led to a compound that was a partial TGR5 agonist. 28 In contrast to tetrazole 25, all other active compounds tested had efficacies in the 80−120% range.…”

Section: ■ Results and Discussionmentioning

confidence: 93%

7-Methylation of Chenodeoxycholic Acid Derivatives Yields a Substantial Increase in TGR5 Receptor Potency

et al. 2019

View full text Add to dashboard Cite

TGR5 agonists are potential therapeutics for a variety of conditions including type 2 diabetes, obesity, and inflammatory bowel disease. After screening a library of chenodeoxycholic acid (CDCA) derivatives, it was determined that a range of modifications could be made to the acid moiety of CDCA which significantly increased TGR5 agonist potency. Surprisingly, methylation of the 7-hydroxyl of CDCA led to a further dramatic increase in potency, allowing the identification of 5.6 nM TGR5 agonist 17.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 93%

7-Methylation of Chenodeoxycholic Acid Derivatives Yields a Substantial Increase in TGR5 Receptor Potency

et al. 2019

View full text Add to dashboard Cite

show abstract

“…They substituted carboxylic tail with amide groups generating compound 1 with good efficacy, FXR selectivity, and pharmacokinetic properties compared to 6-ECDCA ( Fig. 2) [25]. The FXR agonists discussed above all contain a steroidal core?.…”

Section: Nuclear Farnesoid X Receptor Fxrmentioning

confidence: 99%

Improving glucose and lipids metabolism: drug development based on bile acid related targets

Shen¹,

Ding²,

Baig³

et al. 2021

CST

View full text Add to dashboard Cite

Bariatric surgery is one of the most effective treatment options for severe obesity and its comorbidities. However, it is a major surgery that poses several side effects and risks which impede its clinical use. Therefore, it is urgent to develop alternative safer pharmacological approaches to mimic bariatric surgery. Recent studies suggest that bile acids are key players in mediating the metabolic benefits of bariatric surgery. Bile acids can function as signaling molecules by targeting bile acid nuclear receptors and membrane receptors, like FXR and TGR5 respectively. In addition, the composition of bile acids is regulated by either the hepatic sterol enzymes such as CYP8B1 or the gut microbiome. These bile acid related targets all play important roles in regulating metabolism. Drug development based on these targets could provide new hope for patients without the risks of surgery and at a lower cost. In this review, we summarize the most updated progress on bile acid related targets and development of small molecules as drug candidates based on these targets.

show abstract

“…However, this is typically difficult because the solubility of acetamide in organic solvents is low, and a large excess of acetamide is necessary to avoid the formation of dialkylated byproducts. [9][10][11][12][13][14][15] Therefore, a three-step transformation involving azidation, reduction, and acetylation is often employed, 16) although this procedure is disadvantageous owing to the formation of an explosive alkyl azide intermediate.…”

Section: Introductionmentioning

confidence: 99%

p-Methoxy- and 2,4-Dimethoxybenzyl N-Acetylcarbamate Potassium Salts: Versatile Reagents for N-Alkylacetamide and p-Methoxy- and 2,4-Dimethoxybenzyl Carbamates

Takeo

Takenaka

Koike

et al. 2022

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

The acetamide moiety is a general functional group present in many natural and pharmaceutical products. Herein, we report two new reagents, p-methoxybenzyl N-acetylcarbamate potassium salt (PM-BENAC-K) and 2,4-dimethoxybenzyl N-acetylcarbamate potassium salt (2,4-DM-BENAC-K), which are refined versions of the benzyl N-acetylcarbamate potassium salt (BENAC-K). These compounds, which we reported as simple equivalents of N-acetamide nucleophiles, are stable and easy-to-handle powders that react with a variety of alkyl halides and sulfonates to afford substituted products in good yields. The products were transformed into N-alkylacetamides after p-methoxybenzyloxycarbonyl (Moz) or 2,4-dimethoxybenzyloxycarbonyl (Dmoz) cleavage under mild acidic conditions. The acetyl groups in the substituted products of PM-and 2,4-DM-BENAC-Ks were removed using K 2 CO 3 in methanol to afford Moz-and Dmoz-protected amines, respectively. Hence, the new BENAC-Ks acted as versatile equivalents of both N-acetamide and Moz/Dmozprotected nitrogen nucleophiles and can be used in synthetic studies of natural and pharmaceutical products.

show abstract

Synthesis and Biological Evaluation of a Series of Bile Acid Derivatives as FXR Agonists for Treatment of NASH

Cited by 18 publications

References 23 publications

7-Methylation of Chenodeoxycholic Acid Derivatives Yields a Substantial Increase in TGR5 Receptor Potency

7-Methylation of Chenodeoxycholic Acid Derivatives Yields a Substantial Increase in TGR5 Receptor Potency

Improving glucose and lipids metabolism: drug development based on bile acid related targets

<i>p</i>-Methoxy- and 2,4-Dimethoxybenzyl <i>N</i>-Acetylcarbamate Potassium Salts: Versatile Reagents for <i>N</i>-Alkylacetamide and <i>p</i>-Methoxy- and 2,4-Dimethoxybenzyl Carbamates

Contact Info

Product

Resources

About