TY - JOUR T1 - Novel Rho Kinase Inhibitors with Anti-inflammatory and Vasodilatory Activities JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 89 LP - 98 DO - 10.1124/jpet.106.110635 VL - 320 IS - 1 AU - Chris Doe AU - Ross Bentley AU - David J. Behm AU - Robert Lafferty AU - Robert Stavenger AU - David Jung AU - Mark Bamford AU - Terry Panchal AU - Eugene Grygielko AU - Lois L. Wright AU - Gary K. Smith AU - Zunxuan Chen AU - Christine Webb AU - Sanjay Khandekar AU - Tracey Yi AU - Robert Kirkpatrick AU - Edward Dul AU - Larry Jolivette AU - Joseph P. Marino, Jr. AU - Robert Willette AU - Dennis Lee AU - Erding Hu Y1 - 2007/01/01 UR - http://jpet.aspetjournals.org/content/320/1/89.abstract N2 - Increased Rho kinase (ROCK) activity contributes to smooth muscle contraction and regulates blood pressure homeostasis. We hypothesized that potent and selective ROCK inhibitors with novel structural motifs would help elucidate the functional role of ROCK and further explore the therapeutic potential of ROCK inhibition for hypertension. In this article, we characterized two aminofurazan-based inhibitors, GSK269962A [N-(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4, 5-c]pyridin-6-yl]oxy}phenyl)-4-{[2-(4-morpholinyl)ethyl]-oxy}benzamide] and SB-7720770-B [4-(7-{[(3S)-3-amino-1-pyrrolidinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine], as members of a novel class of compounds that potently inhibit ROCK enzymatic activity. GSK269962A and SB-772077-B have IC50 values of 1.6 and 5.6 nM toward recombinant human ROCK1, respectively. GSK269962A also exhibited more than 30-fold selectivity against a panel of serine/threonine kinases. In lipopolysaccharide-stimulated monocytes, these inhibitors blocked the generation of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α. Furthermore, both SB-772077-B and GSK269962A induced vasorelaxation in preconstricted rat aorta with an IC50 of 39 and 35 nM, respectively. Oral administration of either GSK269962A or SB-772077-B produced a profound dose-dependent reduction of systemic blood pressure in spontaneously hypertensive rats. At doses of 1, 3, and 30 mg/kg, both compounds induced a reduction in blood pressure of approximately 10, 20, and 50 mm Hg. In addition, administration of SB-772077-B also dramatically lowered blood pressure in DOCA salt-induced hypertensive rats. SB-772077-B and GSK269962A represent a novel class of ROCK inhibitors that have profound effects in the vasculature and may enable us to further evaluate the potential beneficial effects of ROCK inhibition in animal models of cardiovascular as well as other chronic diseases. The American Society for Pharmacology and Experimental Therapeutics ER -