Zafirlukast Is a Dual Modulator of Human Soluble Epoxide Hydrolase and Peroxisome Proliferator-Activated Receptor γ

Frontiers in Pharmacology

Jan Heering¹  Thorsten J. Maier²  Gerd Geisslinger³  Carlo Angioni³  Astrid S. Kahnt⁴  Olaf Diehl⁴  Daniel Merk⁴  Tim Schader⁴  Sandra K. Wittmann⁴  Ewgenij Proschak⁴  Tamara Göbel⁴  Ramona Kottke⁴  Dieter Steinhilber⁴  Lilia Weizel⁴  Manfred Schubert-Zsilavecz⁴  Estel.la Buscato⁴ 

[1]Branch for Translational Medicine and Pharmacology, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Frankfurt am Main, Germany

[2]Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany

[3]Faculty of Medicine, Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, ZAFES, Frankfurt am Main, Germany

[4]Institute of Pharmaceutical Chemistry/ZAFES, Goethe University Frankfurt, Frankfurt am Main, Germany

关键词: PPARγ;    soluble epoxide hydrolase;    zafirlukast;    montelukast;    pranlukast;    metabolic syndrome;   

DOI  :  10.3389/fphar.2019.00263

来源: DOAJ

【 摘 要 】

Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC50 values of 1.9, 14.1, and 0.8 μM, respectively. In contrast, only montelukast and zafirlukast activated PPARγ in the reporter gene assay with EC50 values of 1.17 μM (21.9% max. activation) and 2.49 μM (148% max. activation), respectively. PPARα and δ were not affected by any of the compounds. The activation of PPARγ was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARγ phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARγ target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARγ cofactor CBP upon ligand binding suggesting that both compounds act as PPARγ modulators. In addition, zafirlukast impaired the TNFα triggered phosphorylation of PPARγ2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARγ modulator representing an excellent starting point for the further development of this compound class.

【 授权许可】

Unknown