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CARDIOVASCULAR

Novel Rho Kinase Inhibitors with Anti-inflammatory and Vasodilatory Activities

Departments of Investigational Biology (C.D., R.B., R.W.), Vascular Biology and Thrombosis (D.J.B., R.L., Z.C., C.W., E.H.), Urology (E.G.), Drug Metabolism (L.J.), and Medicinal Chemistry (R.S., J.P.M., D.L.), Centres of Excellence for Cardiovascular Urogenital Drug Discovery; Department of Chemistry (M.B., T.P.), Centre of Excellence for Neurology Drug Discovery; and Departments of Gene Expression and Protein Biochemistry (S.K., T.Y., R.K., E.D.), Screening & Compound Profiling (L.L.W., G.K.S.) and Chemistry (D.J.), Discovery Research, GlaxoSmithKline Pharmaceuticals Inc., King of Prussia, Pennsylvania

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-. 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.

Address correspondence to: Dr. Erding Hu, Mail Code UW2510, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406. E-mail: erding.hu-1{at}gsk.com