Abstract：
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 4e, demonstrating better PDE4B (IC50 = 10.0 nM) and PDE4D (IC50 = 15.2 nM) inhibitor activity as a potential anti-hepatic sepsis drug in this study. Compared with FCPR16 and Z19153, 4e displayed improved oral bioavailability (F = 66 %) and longer half-life (t1/2 = 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, 4e exhibited excellent hepatoprotective activity against hepatic sepsis by decreasing ALT and AST levels and inflammatory infiltrating areas.
摘要：
败血症可迅速导致危重患者死亡，虽然肝损伤可以加速脓毒症的进展，有必要探索治疗肝败血症的新策略。PDE4已被确定为治疗肝损伤的潜在靶标。先导化合物FCPR16和Z19153的支架跳跃导致发现了新型7-甲氧基苯并呋喃PDE4抑制剂4e，在本研究中,PDE4B(IC50=10.0nM)和PDE4D(IC50=15.2nM)抑制剂活性较好,是一种潜在的抗肝败血症药物.与FCPR16和Z19153相比，4e在SD大鼠中显示出改善的口服生物利用度（F=66％）和更长的半衰期（t1/2=2.0h），这意味着它可以更容易地管理，并具有更持久的效果。在D-GalN/LPS诱导的肝损伤模型中,通过降低ALT和AST水平以及炎性浸润区域,4e表现出针对肝败血症的优异的肝保护活性。
