Evaluating a Specific Dual ROCK Inhibitor against Bleomycin-Induced Idiopathic Pulmonary Fibrosis in Rats.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease. Rho-associated protein kinases (ROCK) 1/2 are promising therapeutic targets for the treatment of IPF. However, a single inhibition of each of them is insufficient to prevent bleomycin-induced lung fibrosis. The current work reported that bleomycin-induced lung fibrosis can be reduced by dual inhibition of ROCK1/2 with compound 1. We evaluated the dual-selective ROCK1/2 inhibition activity of compound 1, its toxicity, and its preliminary efficacy on bleomycin-induced lung fibrosis. In vitro, compound 1 served as the ROCK1/2 inhibitor with half-maximal inhibitory concentration (IC50) values of 165 ±10.4 nM for ROCK1 and 16.1 ± 2.82 nM for ROCK2. In NIH/3T3 cells, compound 1 inhibited the mRNA expression of COL 1A1 and α-SMA. At therapeutic levels, compound 1 exhibited neither hepatic nor cardiac toxicity, also no CYP450 enzyme inhibition. In vivo, compound 1 had good pharmacokinetic properties, and its oral administration reduced bleomycin-induced pulmonary fibrosis in rats. All the outcomes prove the drug-like characteristics of compound 1 for the treatment of IPF.