SAR407899

SAR407899 is a selective, potent and ATP-competitive ROCK inhibitor, with an IC₅₀ of 135 nM for ROCK-2, and K_is of 36 nM and 41 nM for human and rat ROCK-2, respectively. SAR407899 shows stable inhibition of migrasome formation. IC50 & Target:IC50: 135 nM (ROCK-2), 102 nM (Human ROCK-2), 276 nM (Human ROCK-1)^[1]
Ki: 36 nM (Human ROCK-2), 41 nM (Rat ROCK-2)^[1] In Vitro:SAR407899 is a potent and ATP-competitive ROCK inhibitor, with K_is of 36 nM and 41 nM for human and rat ROCK-2, respectively. SAR407899 inhibits ROCK-2 better than ROCK-1, with IC₅₀s of 102 ± 19 nM and 276 ± 26 nM, respectively, in the presence of 40 μM ATP. SAR407899 also less potently inhibits PKC-Δ and MSK-1, with IC₅₀s of 5.4 and 3.1 μM, respectively. SAR407899 (0.1, 0.3, 1.0, and 3.0 μM) specifically inhibits the ROCK-mediated phosphorylation of MYPT^T696 in HeLa cells stimulated with PHEN, and shows such effects at 1 μM and 10 μM in primary rat aortic smooth muscle cells. SAR407899 (3 μM) completely blocks thrombin-induced shrinkage of human umbilical vein endothelial cells (HUVECs) and stress fiber formation. SAR407899 concentration-dependently inhibits 5-bromodeoxyuridine incorporation into the cells with an IC₅₀ of 5.0 ± 1.3 μM. SAR407899 also effectively inhibits THP-1 migration with an IC₅₀ of 2.5 ± 1.0 μM. SAR407899 shows a potent vasorelaxant activity in a broad variety of isolated arteries taken from different vascular beds and species, with a range of IC₅₀ values between 122 and 280 nM^[1]. SAR407899 dose-dependently relaxes the phenylephrine pre-contracted smooth muscle, with IC₅₀s of 0.07 and 0.05 μM, respectively^[2]. In Vivo:SAR407899 (3 mg/kg, i.v.) inhibits ROCK-mediated phosphorylation of MYPT^T696 in thoracic aorta of spontaneously hypertensive rats (SHRs). SAR407899 (0.01-0.30 mg/kg, i.v.) efficiently reduces pressor responses to vasoconstrictor agents in rats. SAR407899 (1, 3, 10, and 30 mg/kg, p.o.) dose dependently lowers blood pressure in hypertensive SHRs^[1]. SAR407899 (1-3 mg/kg, i.v. or 3, 10 mg/kg, p.o.) increases the length of the penis in healthy rabbits. SAR407899 (3-10 mg/kg, p.o.) also dose-dependently increases penile length in diabetic rabbits^[2].