SAR407899 exhibits strong inhibitory action against ROCK by competing with ATP, showing Ki values of 36 nM for human ROCK-2 and 41 nM for rat ROCK-2. It more effectively inhibits ROCK-2 compared to ROCK-1, with inhibition concentrations (IC50s) of 102 ± 19 nM and 276 ± 26 nM, respectively, under conditions of 40 μM ATP. Moreover, SAR407899 inhibits PKC-Δ and MSK-1 with lower potency, having IC50s of 5.4 and 3.1 μM, respectively. In HeLa cells activated by PHEN, SAR407899 at concentrations of 0.1, 0.3, 1.0, and 3.0 μM selectively prevents ROCK-driven phosphorylation of MYPTT696, and demonstrates effectiveness at 1 μM and 10 μM in rat primary aortic smooth muscle cells. A concentration of 3 μM of SAR407899 fully inhibits the contraction of human umbilical vein endothelial cells (HUVECs) triggered by thrombin and formation of stress fibers. It also concentration-dependently reduces 5-bromodeoxyuridine integration into cells with an IC50 of 5.0 ± 1.3 μM and efficiently blocks THP-1 cell migration with an IC50 of 2.5 ± 1.0 μM. SAR407899 shows strong vasorelaxation effects across various isolated arteries from different species and vascular beds, with IC50 values ranging from 122 to 280 nM[1]. Furthermore, SAR407899 relaxes smooth muscle pre-contracted with phenylephrine in a dose-dependent manner, with IC50s of 0.07 and 0.05 μM[2].
体内研究
Administered at 3 mg/kg intravenously, SAR407899 hinders ROCK-dependent phosphorylation of MYPTT696 in the thoracic aorta of spontaneously hypertensive rats (SHRs), and at doses ranging from 0.01 to 0.30 mg/kg intravenously, it effectively mitigates pressor reactions to vasoconstrictive substances in rats. Oral doses of 1, 3, 10, and 30 mg/kg of SAR407899 lower blood pressure in SHRs in a dose-dependent fashion[1].
SAR407899 enhances penile length in healthy rabbits when given at doses of 1-3 mg/kg intravenously or 3, 10 mg/kg orally, and similarly increases penile length in diabetic rabbits at doses of 3-10 mg/kg orally in a dose-dependent manner[2].
体外研究
SAR407899 exhibits strong inhibitory action against ROCK by competing with ATP, showing Ki values of 36 nM for human ROCK-2 and 41 nM for rat ROCK-2. It more effectively inhibits ROCK-2 compared to ROCK-1, with inhibition concentrations (IC50s) of 102 ± 19 nM and 276 ± 26 nM, respectively, under conditions of 40 μM ATP. Moreover, SAR407899 inhibits PKC-Δ and MSK-1 with lower potency, having IC50s of 5.4 and 3.1 μM, respectively. In HeLa cells activated by PHEN, SAR407899 at concentrations of 0.1, 0.3, 1.0, and 3.0 μM selectively prevents ROCK-driven phosphorylation of MYPTT696, and demonstrates effectiveness at 1 μM and 10 μM in rat primary aortic smooth muscle cells. A concentration of 3 μM of SAR407899 fully inhibits the contraction of human umbilical vein endothelial cells (HUVECs) triggered by thrombin and formation of stress fibers. It also concentration-dependently reduces 5-bromodeoxyuridine integration into cells with an IC50 of 5.0 ± 1.3 μM and efficiently blocks THP-1 cell migration with an IC50 of 2.5 ± 1.0 μM. SAR407899 shows strong vasorelaxation effects across various isolated arteries from different species and vascular beds, with IC50 values ranging from 122 to 280 nM[1].
Furthermore, SAR407899 relaxes smooth muscle pre-contracted with phenylephrine in a dose-dependent manner, with IC50s of 0.07 and 0.05 μM[2].
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