Novel Rho Kinase Inhibitors with Anti-inflammatory and Vasodilatory Activities

Abstract

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-, as members of a novel class of compounds that potently inhibit ROCK enzymatic activity. GSK269962A and SB-772077-B have IC 50 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 IC 50 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.Rho kinase (ROCK) belongs to a family of Ser/Thr protein kinases that is primarily activated via interaction with the small GTP-binding protein RhoA. Growing evidence suggests that RhoA and ROCK participate in a variety of important physiological functions in vasculature, including smooth muscle contraction, cell proliferation, cell adhesion, migration, and many aspects of inflammatory responses (Riento and Ridley, 2003). Two isoforms, ROCK1 and ROCK2, have been identified (Ishizaki et al., 1996;Leung et al., 1996;Matsui et al., 1996). They share significant sequence homolArticle, publication date, and citation information can be found at

Cardiovascular effects of a novel potent and highly selective azaindole‐based inhibitor of Rho‐kinase

“…Interestingly, in conscious normotensive and hypertensive rats heart rate was only slightly and transiently increased at the highest dose. Recently, the vasodilator effects of two structurally different ROCK inhibitors were described (Doe et al, 2007). Both ROCK inhibitors are potent and selective compounds (Doe et al, 2007;Goodman et al, 2007;Stavenger et al, 2007), that show comparable strong blood pressure lowering effects in different animal models of hypertension.…”

Inhibiting nonmuscle myosin II impedes inflammatory infiltration and ameliorates progressive renal disease

“…12 Blebbistatin was recently found to mitigate the migration of a variety of immune competent cells, [13][14][15][16][17][18] suggesting that NMII is crucial for immunocyte motility. Consistently, a growing body of evidence reveals that indirect inactivation of NMII through inhibition of myosin light chain kinase 19,20 or Rho kinase 18,[21][22][23][24] impaired leukocyte migration and improved inflammation. Nevertheless, the exact role of NMII in mediating leukocytes' inflammatory response remains uncertain.…”

“…Indeed, evidence suggests that inhibition of Rho kinase, a regulator myosin phosporylation, suppressed myosin activity and disrupted macrophage migration. 18,21 In vivo, long-term treatment with Rho kinase inhibitor attenuated coronary vascular inflammation and induced a regression of atherosclerotic coronary lesions, 23,24 possibly by preventing migration of macrophages. 18,24 Nevertheless, the in vivo effect of direct NMII inhibition by blebbistatin has barely been investigated.…”

Modern Methods of Controlling Wound Healing After Fistulizing Glaucoma Surgery. Anti-Inflammatory Drugs and New Trends

“…По данным ги-стологических исследований фильтрационные подушки, обработанные ингибиторами ROCK, характеризуются менее выраженным воспалением, в них медленнее идет ангиогенез и откладывается меньше коллагена [11]. Экс-периментальные данные указывают на то, что ROCK не только регулирует активность цитоскелета, но и играет важную роль в патогенезе воспаления [12]. Таким об-разом, каскад Rho-ROCK задействован в различных процессах, которые имеют важное значение для раноза-живления, а ингибирование ROCK может считаться пер-спективной стратегией модулирования ранозаживления после антиглаукомных операций.…”