SAR407899

SAR407899 is an ATP-competitive inhibitor of the Rho-associated kinases ROCK1 and ROCK2 (IC₅₀s = 102 and 276 nM, respectively at a concentration of 40 μM ATP).¹ SAR407899 is selective for ROCK over 79 other kinases at IC₅₀ values up to 10 μM but had IC₅₀ values ranging from 1 to 10 μM for RSK, PKB, PKCδ, and MSK-1. It is also selective for ROCK over 115 receptor and enzyme targets at IC₅₀ values up to 10 μM, but it does inhibit the serotonin transporter and µ-opioid receptors with IC₅₀ values of 1.1 and 8.9 μM, respectively. In vitro, SAR407899 inhibits ROCK-mediated phosphorylation of myosin phosphatase (MYPT), thrombin-induced stress fiber formation, PDGF-induced proliferation, and monocyte chemotactic protein-1-stimulated chemotaxis. SAR407899 relaxes precontracted isolated arteries from various species (IC₅₀s = 122-280 nM) and precontracted corpora cavernosa in both healthy and diabetic animals (IC₅₀s = 0.05-0.42 μM).¹,² It inhibits constriction of rat and human arteries induced by endothelin-1 (ET-1; E_maxs = 24-83% of control).³

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1. Löhn, M., Plettenburg, O., Ivashchenko, Y., et al. Pharmacological characterization of SAR407899, a novel rho-kinase inhibitor. Hypertension 54(3), 676-683 (2009).

2. Guagnini, F., Ferazzini, M., Grasso, M., et al. Erectile properties of the Rho-kinase inhibitor SAR407899 in diabetic animals and human isolated corpora cavernosa. J. Transl. Med. 10, 59 (2012).

3. Grisk, O., Schlüter, T., Reimer, N., et al. The Rho kinase inhibitor SAR407899 potently inhibits endothelin-1-induced constriction of renal resistance arteries. J. Hypertens. 30(5), 980-989 (2012).