Abstract：
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC50 of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF.
摘要：
特发性肺纤维化(IPF)是一种慢性,进步,和高死亡率的肺病。虽然抗纤维化药物吡非尼酮和尼达尼布可以减缓肺功能下降的速度，这种情况通常会导致呼吸衰竭和死亡。因此,迫切需要新的治疗IPF的方法和新的治疗药物。选择性PDE4抑制剂在IPF模型中具有体内和体外抗纤维化作用。但大多数PDE4抑制剂的临床应用受到其意想不到的严重副作用如恶心、呕吐,和腹泻。在这里，天然产物MoracinM的基于结构的优化导致了一种新型的2-芳基苯并呋喃作为有效的PDE4抑制剂。最有效的抑制剂L13的IC50为36±7nM，在PDE家族中具有显着的选择性，在博来霉素诱导的IPF小鼠模型中，L13·柠檬酸盐（10.0mg/kg）的给药表现出与吡非尼酮（300mg/kg）相当的抗肺纤维化作用。表明L13是治疗IPF的潜在铅。
