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