Discovery of a Novel Selective Dual Peroxisome Proliferator-Activated Receptor α/δ Agonist for the Treatment of Primary Biliary Cirrhosis

Jiang, Zhigan; Liu, Xing; Yuan, Zhiliang; He, Haiying; Wang, Jing; Zhang, Xiao; Gong, Zongqiang; Hou, Lijuan; Shen, Liang; Guo, Fengxun; Zhang, Jiliang; Wang, Jianhua; Xu, Deming; Liu, Zhuowei; Li, Haijun; Chen, Xiaoxin; Long, C. S.; Li, Jian; Chen, Shuhui

doi:10.1021/acsmedchemlett.9b00189

Cited by 5 publications

(6 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some PPARs agonists are presented in Figure . Among them, compounds 1 ( GFT-505 ) and 3 – 10 are PPARα/δ dual agonists, − while compound 2 ( IVA-337 ) is a pan-PPAR agonist entering the phase II clinical trial for NASH treatment (NCT03008070). GFT-505 is the only PPARα/δ dual agonist entering the phase III clinical trial for NASH treatment (NCT02704403).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARα/δ Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis

et al. 2022

View full text Add to dashboard Cite

Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for nonalcoholic steatohepatitis (NASH). However, PPARα/δ dual agonist GFT-505 exhibited poor anti-NASH effects in a phase III clinical trial, probably due to its weak PPARα/δ agonistic activity and poor metabolic stability. Other reported PPARα/δ dual agonists either exhibited limited potency or had unbalanced PPARα/δ agonistic activity. Herein, we report a series of novel triazolone derivatives as PPARα/δ dual agonists. Among them, compound H11 exhibited potent and well-balanced PPARα/δ agonistic activity (PPARα EC50 = 7.0 nM; PPARδ EC50 = 8.4 nM) and a high selectivity over PPARγ (PPARγ EC50 = 1316.1 nM) in PPAR transactivation assays. The crystal structure of PPARδ in complex with H11 revealed a unique PPARδ-agonist interaction. H11, which had excellent PK properties and a good safety profile, showed potent in vivo anti-NASH effects in preclinical models. Together, H11 holds a great promise for treating NASH or other inflammatory and fibrotic diseases.

show abstract

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARα/δ Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The ANIT-induced mouse model is the widely used model for studying cholestatic liver diseases since the pathological features of this mouse model (e.g., bile acid accumulation, hepatocyte damage, and inflammatory infiltration) are similar to those observed in patients with CLD. − As shown in Figure A depicting the experiment procedure schemes, mice were orally administrated daily with V1 (0.03, 0.1 mg/kg), H11 (3 mg/kg), or elafibranor (30 mg/kg) three times, then euthanized 48 h after the administration of 80 mg/kg ANIT. We chose elafibranor at a dose of 30 mpk as it was reported to show an anti-CLD effect at 30 mpk . And the dose of lead compound H11 in in vivo experiments was established according to our previous work …”

Section: Resultsmentioning

confidence: 99%

“…To investigate the impact of the lengths of the carbon linkers attached to the hydantoin ring on the potency, compounds 34−38 (Table 2) were designed based on 15. Of note, when the methylene linker of 15 was deleted (34,37) or extended (35,36), the PPARα/δ agonistic activity dramatically decreased. Replacement of the p-CF 3 -phenyl group of 15 with the p-CF 3 -benzyl group also led to a significant loss of potency (38).…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of the First Subnanomolar PPARα/δ Dual Agonist for the Treatment of Cholestatic Liver Diseases

et al. 2023

View full text Add to dashboard Cite

Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are considered as potential drug targets for cholestatic liver diseases (CLD) via ameliorating hepatic cholestasis, inflammation, and fibrosis. In this work, we developed a series of hydantoin derivatives as potent PPARα/δ dual agonists. Representative compound V1 exhibited PPARα/δ dual agonistic activity at the subnanomolar level (PPARα EC50 = 0.7 nM; PPARδ EC50 = 0.4 nM) and showed excellent selectivity over other related nuclear receptors. The crystal structure revealed the binding mode of V1 and PPARδ at 2.1 Å resolution. Importantly, V1 demonstrated excellent pharmacokinetic (PK) properties and a good safety profile. Notably, V1 showed potent anti-CLD and antifibrotic effects in preclinical models at very low doses (0.03 and 0.1 mg/kg). Collectively, this work provides a promising drug candidate for treating CLD and other hepatic fibrosis diseases.

show abstract

“…When subjected to cholic acid dietary challenge, PPARα −/− mice showed bile acid accumulation in their livers, resulting from decreasing levels of mRNA-encoding transporters, including Abcb11, Abcb4, Abca1, Abcg5, and Abcg8 ( Li et al, 2012 ). In the rat primary biliary cirrhosis model, a novel PPARα/δ dual agonist 5c demonstrated excellent in vivo efficacy ( Jiang et al, 2019 ). Fibrate drugs are PPARα agonists and are mainly used as cholesterol-lowering drugs for patients with elevated triglycerides.…”

Section: Peroxisome Proliferator-activated Receptor Alpha As a Therap...mentioning

confidence: 99%

PPARα: A potential therapeutic target of cholestasis

Zhang

Han

2022

Front. Pharmacol.

View full text Add to dashboard Cite

The accumulation of bile acids in the liver leads to the development of cholestasis and hepatocyte injury. Nuclear receptors control the synthesis and transport of bile acids in the liver. Among them, the farnesoid X receptor (FXR) is the most common receptor studied in treating cholestasis. The activation of this receptor can reduce the amount of bile acid synthesis and decrease the bile acid content in the liver, alleviating cholestasis. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) have a FXR excitatory effect, but the unresponsiveness of some patients and the side effect of pruritus seriously affect the results of UDCA or OCA treatment. The activator of peroxisome proliferator-activated receptor alpha (PPARα) has emerged as a new target for controlling the synthesis and transport of bile acids during cholestasis. Moreover, the anti-inflammatory effect of PPARα can effectively reduce cholestatic liver injury, thereby improving patients’ physiological status. Here, we will focus on the function of PPARα and its involvement in the regulation of bile acid transport and metabolism. In addition, the anti-inflammatory effects of PPARα will be discussed in some detail. Finally, we will discuss the application of PPARα agonists for cholestatic liver disorders.

show abstract

Discovery of a Novel Selective Dual Peroxisome Proliferator-Activated Receptor α/δ Agonist for the Treatment of Primary Biliary Cirrhosis

Cited by 5 publications

References 43 publications

Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARα/δ Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis

Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARα/δ Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis

Discovery of the First Subnanomolar PPARα/δ Dual Agonist for the Treatment of Cholestatic Liver Diseases

PPARα: A potential therapeutic target of cholestasis

Contact Info

Product

Resources

About