Discovery of new and highly effective quadruple FFA1 and PPARα/γ/δ agonists as potential anti-fatty liver agents

Zhou, Zongtao; Ren, Qiang; Jiao, Shixuan; Cai, Zongyu; Geng, Xue; Deng, Liming; Wang, Bin; Hu, Lijun; Zhang, Luyong; Yang, Ying; Li, Zheng

doi:10.1016/j.ejmech.2021.114061

Cited by 8 publications

(7 citation statements)

References 53 publications

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“…A preclinical study revealed that ZLY18 (a quadruple FFA1/PPAR-α/γ/δ agonist) significantly reduced steatosis, hepatocyte balloon, inflammation, and liver fibrosis in the NASH models, and represented a novel and highly promising quad FFA1/PPAR-α/γ/δ agonist warranting further investigation and development. 572 …”

Section: Novel Signaling Pathways and Pharmacological Targetsmentioning

confidence: 99%

Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

Poulsen

et al. 2022

Sig Transduct Target Ther

133

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Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut–liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.

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Section: Novel Signaling Pathways and Pharmacological Targetsmentioning

confidence: 99%

Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

Poulsen

et al. 2022

Sig Transduct Target Ther

133

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“…In the NASH model, ZLY18 reversed hyperlipidemia to an almost normal level, and significantly decreased hepatocellular ballooning, inflammation, and liver fibrosis even better than RLA8 228 . In addition, ZLY18 is more effective than PPARα agonists in the prevention of CCl 4 -induced liver fibrosis 228 …”

Section: Pparα Modulators In Preclinical Studiesmentioning

confidence: 92%

“…Results from 2 mouse NASH models (induced by a methionine/choline-deficient diet or by a high-fat diet) showed that RLA8 reversed NASH-induced liver damage such as steatosis, inflammation, and fibrosis by reducing lipotoxicity and oxidative stress through activating PPARs and GPR40 227 . Based on this agonist, a newly developed quadruple ZLY18 exhibited far stronger lipid-lowering effects and twice higher metabolic half-life than that of RLA8 228 . In the NASH model, ZLY18 reversed hyperlipidemia to an almost normal level, and significantly decreased hepatocellular ballooning, inflammation, and liver fibrosis even better than RLA8 228 .…”

Section: Pparα Modulators In Preclinical Studiesmentioning

confidence: 99%

“…Based on this agonist, a newly developed quadruple ZLY18 exhibited far stronger lipid-lowering effects and twice higher metabolic half-life than that of RLA8 228 . In the NASH model, ZLY18 reversed hyperlipidemia to an almost normal level, and significantly decreased hepatocellular ballooning, inflammation, and liver fibrosis even better than RLA8 228 . In addition, ZLY18 is more effective than PPARα agonists in the prevention of CCl 4 -induced liver fibrosis 228 …”

Section: Pparα Modulators In Preclinical Studiesmentioning

confidence: 99%

“…[228] In addition, ZLY18 is more effective than PPARα agonists in the prevention of CCl 4 -induced liver fibrosis. [228] In addition to synthetic PPARα agonists, PPARα seems to mediate the beneficial effects of a series of chemicals or oligonucleotides on ameliorating fibrosis (Table 1). For example, the lipids oleoylethanolamide and palmitoylethanolamide are representative endogenous PPARα ligands.…”

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confidence: 99%

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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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Privileged scaffolds in anti-diabetic drug discovery

Chen

Zhang

2023

Privileged Scaffolds in Drug Discovery

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Discovery of new and highly effective quadruple FFA1 and PPARα/γ/δ agonists as potential anti-fatty liver agents

Cited by 8 publications

References 53 publications

Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

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

Privileged scaffolds in anti-diabetic drug discovery

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