Identification of Novel Imidazo[1,2‑b]pyridazine Derivatives as Selective ROCK2 Inhibitors for the Treatment of Pulmonary Fibrosis

Rho-associated coiled-coil containing protein kinase 2 (ROCK2) has been identified as a promising target for the treatment of pulmonary fibrosis (PF). In this study, a series of novel imidazo[1,2-b]pyridazine derivatives were designed as selective ROCK2 inhibitors. Through comprehensive investigation of SARs, compounds A25 and A26 exhibited superior ROCK2 inhibitory potency (IC50 = 7.0 and 8.7 nM, respectively) and excellent isoform selectivity (SI = 200/138). In bleomycin-induced PF mice models, administration of A25 and A26 resulted in a pronounced reduction of collagen deposition and a significant reversal of fibrotic progression. Mechanism study confirmed that A25 exerted antifibrotic effects via the TGF-β/Smad and ROCK2/STAT3 signaling pathways. Furthermore, A25 exhibited a favorable safety profile, showing low hERG channel inhibition and almost no pathological alterations in major organs. Overall, A25 was identified as a promising lead compound for the development of selective ROCK2 inhibitors for PF therapy.

含Rho相关卷曲螺旋的蛋白激酶2（ROCK2）已被确定为治疗肺纤维化（PF）的极具潜力的靶点。本研究设计了一系列新型咪唑并[1,2-b]哒嗪衍生物作为选择性ROCK2抑制剂。通过对构效关系（SARs）的全面探究，化合物A25与A26展现出优异的ROCK2抑制活性（半数抑制浓度IC50分别为7.0 nM与8.7 nM），同时具备极佳的亚型选择性（选择性指数SI为200/138）。在博来霉素诱导的肺纤维化小鼠模型中，给予A25与A26可显著减少胶原沉积，并有效逆转纤维化进程。机制研究证实，A25通过转化生长因子β（TGF-β）/Smad及ROCK2/STAT3信号通路发挥抗纤维化作用。此外，A25展现出良好的安全性谱，对hERG通道抑制作用较弱，且主要脏器几乎未出现病理改变。综上，A25被确定为极具潜力的先导化合物，可用于开发治疗肺纤维化的选择性ROCK2抑制剂。