Doe Chris, Bentley Ross, Behm David J, Lafferty Robert, Stavenger Robert, Jung David, Bamford Mark, Panchal Terry, Grygielko Eugene, Wright Lois L, Smith Gary K, Chen Zunxuan, Webb Christine, Khandekar Sanjay, Yi Tracey, Kirkpatrick Robert, Dul Edward, Jolivette Larry, Marino Joseph P, Willette Robert, Lee Dennis, Hu Erding
Department of Investigational Biology, Centres of Excellence for Cardiovascular Urogenital Drug Discovery, Discovery Research, GlaxoSmithKline Pharmaceuticals Inc., King of Prussia, PA 19406, USA.
J Pharmacol Exp Ther. 2007 Jan;320(1):89-98. doi: 10.1124/jpet.106.110635. Epub 2006 Oct 3.
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-alpha. 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.
Rho激酶（ROCK）活性增强会导致平滑肌收缩并调节血压稳态。我们推测，具有新型结构基序的强效且选择性的ROCK抑制剂将有助于阐明ROCK的功能作用，并进一步探索ROCK抑制对高血压的治疗潜力。在本文中，我们对两种基于氨基呋咱的抑制剂进行了表征，即GSK269962A [N-(3-{[2-(4-氨基-1,2,5-恶二唑-3-基)-1-乙基-1H-咪唑并[4,5-c]吡啶-6-基]氧基}苯基)-4-{[2-(4-吗啉基)乙基]-氧基}苯甲酰胺]和SB-7720770-B [4-(7-{[(3S)-3-氨基-1-吡咯烷基]羰基}-1-乙基-1H-咪唑并[4,5-c]吡啶-2-基)-1,2,5-恶二唑-3-胺]作为一类新型化合物的成员，这类化合物能有效抑制ROCK酶活性。GSK269962A和SB-772077-B对重组人ROCK1的IC50值分别为1.6 nM和5.6 nM。GSK269962A对一组丝氨酸/苏氨酸激酶也表现出超过30倍的选择性。在脂多糖刺激的单核细胞中，这些抑制剂可阻断炎性细胞因子如白细胞介素-6和肿瘤坏死因子-α的产生。此外，SB-772077-B和GSK269962A均可诱导预收缩大鼠主动脉血管舒张，IC50分别为39 nM和35 nM。口服GSK269962A或SB-772077-B均可使自发性高血压大鼠的全身血压产生显著的剂量依赖性降低。在1、3和30 mg/kg的剂量下，两种化合物均可使血压降低约10、20和50 mmHg。此外，给予SB-772077-B也可显著降低去氧皮质酮盐诱导的高血压大鼠的血压。SB-772077-B和GSK269962A代表了一类新型的ROCK抑制剂，它们在脉管系统中具有深远影响，可能使我们能够在心血管以及其他慢性疾病的动物模型中进一步评估ROCK抑制的潜在有益作用。
