Identification of Novel Imidazo[1,2- <i>b</i> ]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-<i>b</i>]pyridazine derivatives were designed as selective ROCK2 inhibitors. Through comprehensive investigation of SARs, compounds <b>A25</b> and <b>A26</b> 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 <b>A25</b> and <b>A26</b> resulted in a pronounced reduction of collagen deposition and a significant reversal of fibrotic progression. Mechanism study confirmed that <b>A25</b> exerted antifibrotic effects via the TGF-β/Smad and ROCK2/STAT3 signaling pathways. Furthermore, <b>A25</b> exhibited a favorable safety profile, showing low hERG channel inhibition and almost no pathological alterations in major organs. Overall, <b>A25</b> was identified as a promising lead compound for the development of selective ROCK2 inhibitors for PF therapy.