Idiopathic pulmonary fibrosis (IPF) is a highly fatal disease that lacks appropriate treatments and highly effective drugs. Many reported indicated that the TGF-β1/Smad3 signaling pathway played a pivotal role in development of IPF. In this case, it was hypothesized that discovery novel compounds to block the TGF-β1/Smad3 signaling pathway might be useful for treatment of IPF. Therefore, a high-throughput screening system based on stably transfected CAGA-NIH3T3 cells was established for discovering lead compounds which could validly suppress the TGF-β1/Smad3 signal path. In this study, a series of novel Pleuromutilin derivatives were prepared and quickly evaluated by high-throughput assay. The lead compound 32 was discovered to be able to remarkably suppress the TGF-β1/Smad3 pathway in vitro. Further biological evaluation revealed that compound 32 could remarkably decrease the myofibroblast stimulation and extracellular matrix (ECM) deposition. More importantly, compound 32 could remarkably mitigate bleomycin (BLM)-triggered lung fibrosis in mice models. Additionally, the lead compound possess excellent pharmacokinetics properties, good oral availability and low toxicity. In general, our study has demonstrated the potency of a novel Pleuromutilin derivative (compound 32), which might be a prospective candidate for developing anti-IPF medicines by suppress the TGF-β1/Smad3 signal pathway.

特发性肺纤维化（IPF）是一种高度致命的疾病，缺乏适当的治疗方法和高效药物。许多报道表明TGF-β1/Smad3信号通路在IPF的发生发展中发挥着关键作用。在这种情况下，假设发现阻断 TGF-β1/Smad3 信号通路的新化合物可能有助于治疗 IPF。因此，建立了基于稳定转染的CAGA-NIH3T3细胞的高通量筛选系统，以发现能够有效抑制TGF-β1/Smad3信号通路的先导化合物。在本研究中，制备了一系列新型截短侧耳素衍生物，并通过高通量测定进行快速评估。先导化合物32被发现能够在体外显着抑制TGF-β1/Smad3途径。进一步的生物学评估表明，化合物32可以显着减少肌成纤维细胞刺激和细胞外基质（ECM）沉积。更重要的是，化合物32可以显着减轻小鼠模型中博莱霉素 (BLM) 引发的肺纤维化。此外，该先导化合物具有优异的药代动力学特性、良好的口服利用度和低毒性。总的来说，我们的研究证明了一种新型截短侧耳素衍生物（化合物32 ）的效力，它可能是通过抑制 TGF-β1/Smad3 信号通路开发抗 IPF 药物的潜在候选者。