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Purpose: To compare the effect of the ROCK inhibitor trans-6-((4-aminocyclohexyl) amino)-5-fluoro-2-methoxynicotinamide (Compound 3) with macitentan in monocrotaline (MCT)-induced PAH in rats.

Methods: We have selected and characterized as pharmacological tool (WO 2010/032875) Compound 3, which resulted a potent ROCK1 (IC50= 12.5±1.0 nM) and 2 (IC50= 7.9±0.9 nM) inhibitor with an excellent selectivity when counter screened against a large (> 400) panel of human kinases. Severe PAH was induced in male Wistar rats by single injection of Monocrotaline (MCT, 60 mg/kg sc). Interventional 2 weeks-treatments with Compound 3 (1 and 3 mg/kg sc, bid), and macitentan (10 mg/kg, po, qd) were started at 14 days after MCT, when the disease is already rapidly progressing. Right ventricle pressure (RVP) in MCT rats (57.3±4.9 mm Hg) was attenuated by the Compound 3 at both doses (1 and 3 mg/kg …