RT Journal Article SR Electronic T1 Novel Rho Kinase Inhibitors with Anti-inflammatory and Vasodilatory Activities JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 89 OP 98 DO 10.1124/jpet.106.110635 VO 320 IS 1 A1 Doe, Chris A1 Bentley, Ross A1 Behm, David J. A1 Lafferty, Robert A1 Stavenger, Robert A1 Jung, David A1 Bamford, Mark A1 Panchal, Terry A1 Grygielko, Eugene A1 Wright, Lois L. A1 Smith, Gary K. A1 Chen, Zunxuan A1 Webb, Christine A1 Khandekar, Sanjay A1 Yi, Tracey A1 Kirkpatrick, Robert A1 Dul, Edward A1 Jolivette, Larry A1 Marino, Joseph P. A1 Willette, Robert A1 Lee, Dennis A1 Hu, Erding YR 2007 UL http://jpet.aspetjournals.org/content/320/1/89.abstract AB 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