Discovery of 7-alkoxybenzofurans as PDE4 inhibitors with hepatoprotective activity in D-GalN/LPS-induced hepatic sepsis,European Journal of Medicinal Chemistry

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Discovery of 7-alkoxybenzofurans as PDE4 inhibitors with hepatoprotective activity in D-GalN/LPS-induced hepatic sepsis
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-06-07 , DOI: 10.1016/j.ejmech.2024.116576
Chuang Xia ₁ , Huizhen Wen ₁ , Lei Zheng ₁ , Yujie Ni ₁ , Huichang Bi ₁ , Haitao Wang ₁ , Jiangping Xu ₁ , Zhong-Zhen Zhou ₁

Affiliation

Sepsis can quickly result in fatality for critically ill individuals, while liver damage can expedite the progression of sepsis, necessitating the exploration of new strategies for treating hepatic sepsis. PDE4 has been identified as a potential target for the treatment of liver damage. The scaffold hopping of lead compounds FCPR16 and Z19153 led to the discovery of a novel 7-methoxybenzofuran PDE4 inhibitor , demonstrating better PDE4B (IC = 10.0 nM) and PDE4D (IC = 15.2 nM) inhibitor activity as a potential anti-hepatic sepsis drug in this study. Compared with FCPR16 and Z19153, displayed improved oral bioavailability (F = 66 %) and longer half-life (t = 2.0 h) in SD rats, which means it can be more easily administered and has a longer-lasting effect. In the D-GalN/LPS-induced liver injury model, exhibited excellent hepatoprotective activity against hepatic sepsis by decreasing ALT and AST levels and inflammatory infiltrating areas.

中文翻译：

发现 7-烷氧基苯并呋喃作为 PDE4 抑制剂，在 D-GalN/LPS 诱导的肝脓毒症中具有保肝活性

脓毒症可迅速导致重症患者死亡，而肝损伤可加速脓毒症的进展，因此需要探索治疗肝脓毒症的新策略。 PDE4已被确定为治疗肝损伤的潜在靶点。先导化合物 FCPR16 和 Z19153 的支架跳跃导致了一种新型 7-甲氧基苯并呋喃 PDE4 抑制剂的发现，证明了作为潜在的抗肝败血症药物具有更好的 PDE4B (IC = 10.0 nM) 和 PDE4D (IC = 15.2 nM) 抑制剂活性。这项研究。与 FCPR16 和 Z19153 相比，在 SD 大鼠中表现出更高的口服生物利用度（F = 66 %）和更长的半衰期（t = 2.0 h），这意味着它更容易给药并且具有更持久的效果。在 D-GalN/LPS 诱导的肝损伤模型中，通过降低 ALT 和 AST 水平以及炎症浸润区域，对肝脓毒症表现出优异的保肝活性。

更新日期：2024-06-07

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