A ROCK1 and ROCK2 inhibitor
TC-S 7001 is an inhibitor of Rho-associated kinase (ROCK; IC50s = 0.6 and 1.1 nM, respectively, for human ROCK1 and ROCK2).1 It is selective for ROCK over myosin light-chain kinase (MLCK) and zipper-interacting protein kinase (ZIP-kinase; IC50s = 7,400 and 4,100 nM, respectively), as well as 110 kinases in a panel at 1-10 ?M, but does inhibit TRK and FLT3 (IC50s = 252 and 303 nM, respectively). TC-S 7001 reduces ROCK2-induced phosphorylation of human myosin-binding subunit (MBS) when used at a concentration of 3 nM and decreases ROCK2 autophosphorylation. It inhibits contraction of isolated rabbit saphenous artery induced by phenylephrine (IC50 = 65 nM) and decreases blood pressure in normotensive and hypertensive rats when administered at doses of 3 and 10 mg/kg. TC-S 7001 also decreases right ventricular systolic pressure and total pulmonary resistance in a rat model of monocrotaline-induced pulmonary hypertension when administered at a dose of 10 mg/kg per day.2
1.Kast, R., Schirok, H., Figueroa-Pérez, S., et al.Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinaseBr. J. Pharmacol.152(7)1070-1080(2007) 2.Dahal, B.K., Kosanovic, D., Pamarthi, P.K., et al.Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertensionEur. Respir. J.36(4)808-818(2010)
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Animal experiment: |
Male Wistar rats weighing 300-350?g are anaesthetized with thiopental 100?mg/kg intraperitoneally (i.p.). A tracheotomy is performed and catheters are inserted into the femoral artery for blood pressure and heart rate measurements and into the femoral vein for test drug administration. The animals are ventilated with room air and their body temperature is controlled. ROCK-IN-2 is administered intravenously (i.v.) in doses of 0.03-0.1?mg/kg. The vehicle Transcutol/Cremophor EL/physiological saline (19/10/80 = v/v/v) without test drug is used as control. The volume administered is 1?mL/kg. Six animals are treated per group[1]. |
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参考文献: [1]. Kast R, et al. Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase. Br J Pharmacol. 2007 Dec;152(7):1070-80. Epub 2007 Oct 15. |
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