Hepatoprotective effects of ZLY16, a dual peroxisome proliferator-activated receptor α/δ agonist, in rodent model of nonalcoholic steatohepatitis

Zhou, Zongtao; Deng, Liming; Hu, Lijun; Ren, Qiang; Cai, Zongyu; Wang, Bin; Li, Zheng; Zhang, Luyong

doi:10.1016/j.ejphar.2020.173300

Cited by 10 publications

(4 citation statements)

References 54 publications

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“…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

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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.

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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

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“…Elafibranor (GFT505), a dual PPARα/δ agonist, demonstrated liver-protective effects on inflammation and fibrosis in different animal models of NASH and liver fibrosis, 216 and the protective effects were mediated by both PPARα-dependent and PPARα-independent mechanisms, 216 indicating that the effects of PPARα and PPARδ on fibrosis may be synergistic. ZLY16, another novel highly potent PPARα/δ agonist, also decreased liver injury biomarkers, hepatic steatosis, inflammation, ballooning, oxidative stress, and fibrosis, and these effects were more favorable than elafibranor 217 . Moreover, an MHY2013 derivative was also identified as a dual PPARα/δ agonist and displayed antifibrotic effects 218 .…”

Section: Pparα Modulators In Preclinical Studiesmentioning

confidence: 98%

“…ZLY16, another novel highly potent PPARα/δ agonist, also decreased liver injury biomarkers, hepatic steatosis, inflammation, ballooning, oxidative stress, and fibrosis, and these effects were more favorable than elafibranor. [217] Moreover, an MHY2013 derivative was also identified as a dual PPARα/δ agonist and displayed antifibrotic effects. [218] A series of novel triazolone derivatives that exhibited more potent and well-balanced PPARα/δ agonistic activity than elafibranor prevented inflammation and liver fibrosis in preclinical models [219] (Table 1).…”

Section: Pparα Modulators In Preclinical Studiesmentioning

confidence: 99%

Hepatic fibrosis: Targeting peroxisome proliferator-activated receptor alpha from mechanism to medicines

et al. 2023

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Liver fibrosis is the result of sustained chronic liver injury and inflammation leading to hepatocyte cell death followed by the formation of fibrous scars, which is the hallmark of NASH and alcoholic steatohepatitis and can lead to cirrhosis, HCC, and liver failure. Although progress has been made in understanding the pathogenesis and clinical consequences of hepatic fibrosis, therapeutic strategies for this disease are limited. Preclinical studies suggest that peroxisome proliferator-activated receptor alpha plays an important role in preventing the development of liver fibrosis by activating genes involved in detoxifying lipotoxicity and toxins, transrepressing genes involved in inflammation, and inhibiting activation of hepatic stellate cells. Given the robust preclinical data, several peroxisome proliferator-activated receptor alpha agonists have been tested in clinical trials for liver fibrosis. Here, we provide an update on recent progress in understanding the mechanisms by which peroxisome proliferator-activated receptor alpha prevents fibrosis and discuss the potential of targeting PPARα for the development of antifibrotic treatments.

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“…Recently, a novel dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ) agonist was synthesized and tested on animal models. Besides protecting the liver from inflammation, and fibrosis, the administration of dual agonists decreased hepatic lipids accumulation, protecting animals from the development of liver steatosis [ 16 , 17 ]. Finally, many efforts have been made to generate pan PPAR agonists combining the pharmacophore motif of PPAR-α, β, and ɣ agonists.…”

Section: Introductionmentioning

confidence: 99%

Natural α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitors: A Source of Scaffold Molecules for Synthesis of New Multitarget Antidiabetic Drugs

et al. 2021

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Diabetes mellitus (DM) represents a group of metabolic disorders that leads to acute and long-term serious complications and is considered a worldwide sanitary emergence. Type 2 diabetes (T2D) represents about 90% of all cases of diabetes, and even if several drugs are actually available for its treatment, in the long term, they show limited effectiveness. Most traditional drugs are designed to act on a specific biological target, but the complexity of the current pathologies has demonstrated that molecules hitting more than one target may be safer and more effective. The purpose of this review is to shed light on the natural compounds known as α-glucosidase and Protein Tyrosine Phosphatase 1B (PTP1B) dual-inhibitors that could be used as lead compounds to generate new multitarget antidiabetic drugs for treatment of T2D.

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Hepatoprotective effects of ZLY16, a dual peroxisome proliferator-activated receptor α/δ agonist, in rodent model of nonalcoholic steatohepatitis

Cited by 10 publications

References 54 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

Hepatic fibrosis: Targeting peroxisome proliferator-activated receptor alpha from mechanism to medicines

Natural α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitors: A Source of Scaffold Molecules for Synthesis of New Multitarget Antidiabetic Drugs

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