Dual Farnesoid X Receptor/Soluble Epoxide Hydrolase Modulators Derived from Zafirlukast.,ChemMedChem

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Dual Farnesoid X Receptor/Soluble Epoxide Hydrolase Modulators Derived from Zafirlukast.
ChemMedChem ( IF 3.6 ) Pub Date : 2019-10-31 , DOI: 10.1002/cmdc.201900576
Simone Schierle ₁ , Moritz Helmstädter ₁ , Jurema Schmidt ₁ , Markus Hartmann ₁ , Maximiliane Horz ₁ , Astrid Kaiser ₁ , Lilia Weizel ₁ , Pascal Heitel ₁ , Anna Proschak ₁ , Victor Hernandez-Olmos ₂ , Ewgenij Proschak ₁ , Daniel Merk ₁

Affiliation

The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non-alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti-NASH effects and thus may generate synergistic efficacy. Here we report dual FXR activators/sEH inhibitors derived from the anti-asthma drug Zafirlukast. Systematic structural optimization of the scaffold has produced favorable dual potency on FXR and sEH while depleting the original cysteinyl leukotriene receptor antagonism of the lead drug. The resulting polypharmacological activity profile holds promise in the treatment of liver-related metabolic diseases.

中文翻译：

双法尼醇 X 受体/可溶性环氧化物水解酶调节剂源自扎鲁司特。

核法尼醇 X 受体 (FXR) 和酶溶性环氧化物水解酶 (sEH) 是治疗非酒精性脂肪性肝炎 (NASH) 等代谢性疾病的经过验证的分子靶标。它们在体内的同时调节已证明具有三联抗 NASH 作用，因此可能产生协同功效。在这里，我们报道了源自抗哮喘药物 Zafirlukast 的双重 FXR 激活剂/sEH 抑制剂。支架的系统结构优化对 FXR 和 sEH 产生了良好的双重功效，同时耗尽了先导药物原有的半胱氨酰白三烯受体拮抗作用。由此产生的多药理活性特征有望治疗肝脏相关代谢疾病。

更新日期：2019-11-20

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