Structural optimization of Moracin M as novel selective phosphodiesterase 4 inhibitors for the treatment of idiopathic pulmonary fibrosis.

[Display omitted] • Structural optimizations of Moracin M resulted in several potent PDE4 inhibitors. • Lead L13 has an IC 50 of 36 ± 7 nM with remarkable selectivity. • L13 exhibits considerable drug-like profile. • L13 ·citrate displayed more significant anti-IPF effect than the marketed drug pirfenidone in vivo. • Docking studies on PDE4- L13 interactions mainly agree with the experimental results. 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 IC 50 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. [ABSTRACT FROM AUTHOR]