A ROCK1 and ROCK2 inhibitor
AS 1892802 is a potent and selective inhibitor of ROCK with IC50 values of 52, 57 and 122 nM for human ROCK2, rat ROCK2 and human ROCK1, respectively [1].
Rho kinase (ROCK) is a serine-threonine kinase and is a downstream effector of Rho, a small GTP-bound protein. ROCK phosphorylates target proteins such as myosin light chain kinase and LIM kinase and regulates cellular shape modification, migration, growth and contraction [2].
AS 1892802 is a potent ROCK inhibitor. AS 1892802 inhibited ROCK1 and ROCK2 with IC50 values of 1.69 and 0.10 μM, respectively [3]. In ATDC5 cells, AS1892802 induce chondrocyte differentiation. In HIG82 cells, AS1892802 significantly inhibited prostaglandin E2 production induced by IL-1β or bradykinin [4].
In both an adjuvant-induced arthritis (AIA) rat model and a monoiodoacetate (MIA) -induced arthritis (MIA) rat model, AS1892802 showed potent antinociceptive effect with ED50 value of 0.15 mg/kg [1]. In monoiodoacetate-induced arthritis and streptozotocin-induced neuropathy models, AS1892802 showed analgesic effect [2]. In MIA-injected rats, the mRNA levels of ROCK I and II increased in knee joints. AS1892802 significantly inhibited cartilage damage in a dose-dependent way [4].
参考文献:
[1].? Yoshimi E, Kumakura F, Hatori C, et al. Antinociceptive effects of AS1892802, a novel Rho kinase inhibitor, in rat models of inflammatory and noninflammatory arthritis. J Pharmacol Exp Ther, 2010, 334(3): 955-963.
[2].? Yoshimi E, Yamamoto H, Furuichi Y, et al. Sustained analgesic effect of the Rho kinase inhibitor AS1892802 in rat models of chronic pain. J Pharmacol Sci, 2010, 114(1): 119-122.
[3].? Li R, Martin MP, Liu Y, et al. Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors. J Med Chem, 2012, 55(5): 2474-2478.
[4].? Takeshita N, Yoshimi E, Hatori C, et al. Alleviating effects of AS1892802, a Rho kinase inhibitor, on osteoarthritic disorders in rodents. J Pharmacol Sci, 2011, 115(4): 481-489.
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