生物活性

• 靶点

  ROCK1 IC50:0.6nM

  ROCK2 IC50:1.1nM

• 描述Rho-kinase (ROCK) is a serine/threonine kinase that has two isoenzymes, ROCK-1 and ROCK-2. ROCK promotes the assembly of actin stress fibers and focal adhesions and regulates cell contraction and motility. ROCK inhibitor is a derivative of azainolde that inhibits the ROCK-1 and ROCK-2 isoenzymes with IC50 values of 0.6 nM and 1.1 nM in an ATP competitive manner. ROCK inhibitor also inhibits TRK and FLT3 with IC50 values of 252 nM and 303 nM, respectively. In addition, ROCK inhibitor inhibits only moderately the L-type calcium channel and the sodium channel with IC50 values of 6.7 μM and 6.8 μM, respectively. In vitro, ROCK inhibitor concentration-dependently inhibited the phenylephrine-induced contraction of rabbit saphenous artery with an IC50 value of 65 nM. In the rat heart langendorff preparation, administration of 10 nM, 100 nM, 1000 nM of ROCK inhibitor resulted in a reduction of the maximal perfusion pressure of 50%, 60% and 65%, respectively. In vivo, intravenous administration of ROCK inhibitor at dose range from 0.03-0.3 mg/kg lowered blood pressure dose-dependently in anaesthetized normotensive rats. Treatment of the conscious normotensive and spontaneously hypertensive rats with ROCK inhibitor at dose range from 1-10 mg/kg via oral administration induced a dose-dependent reduction of blood pressure, without inducing a significant reflex increase in heart rate. In addition, intravenous administration of ROCK inhibitor at dose of 0.1 and 0.3 mg/kg decreased mean arterial blood pressure in anaesthetized dog^[1].
• 作用机制ROCK inhibitor interacts with the ATP-binding site of ROCK and interferes with ATP binding in a competitive manner^[1].

• 动物研究
  剂量	Rat: 0.03 mg/kg - 0.1 mg/kg[1] (i.v.); 3 mg/kg, 10 mg/kg[1] (p.o.); 1 μg/kg - 100 μg/kg[2] (s.c.) Mice[3]: 30 mg/kg/day (p.o.) Dog[1]: 0.05 mg/kg (i.v.)
  给药途径	i.v., p.o., s.c.
  动物药代数据	Animal Mice[1] Rats[1] Dogs[1] Dose 0.5 mg/kg 0.5 mg/kg (i.v.) 0.910 mg/kg (p.o.) 0.05 mg/kg (i.v.) 0.10 mg/kg (p.o.) Administration i.v. i.v. p.o. i.v. p.o. F 48.0% (p.o.) 73.2% (p.o.) T1/2 1.50 h 1.24 h (i.v.) 1.16 h (p.o.) 1.24 h (i.v.) 7.83 h (p.o.) AUC 0.264 mg/h 0.402 mg/h (i.v.) 0.352 mg/h (p.o.) 0.215 mg/h (i.v.) 0.315 mg/h (p.o.) CL 1.90 L/h/kg 1.20 L/h/kg (i.v.) 0.233 L/h/kg (i.v.) Cmax 0.0808 mg/l (p.o.) 0.0403 mg/l (p.o.) Vss 2.20 L/kg 1.60 L/kg (i.v.) 0.832 L/kg (i.v.) Tmax 2.00 h (p.o.) 0.794 h (p.o.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02165215	Colitis, Ulcerative	Phase 3	Recruiting	August 20, 2020	-
  NCT01701817	-	-	Completed	-	-
  NCT01272037	Ductal Breast Carcinoma In Sit... more >>u Estrogen Receptor and/or Progesterone Receptor Positive HER2/Neu Negative Invasive Breast Carcinoma Multicentric Breast Carcinoma Multifocal Breast Carcinoma Synchronous Bilateral Breast Carcinoma Collapse <<	Phase 3	Active, not recruiting	-	-

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• 参考文献

• [1] Kast R, Schirok H, Figueroa-Pérez S, et al. Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase. Br J Pharmacol. 2007;152(7):1070–1080

  [2] Lasker GF, Pankey EA, et al. The selective Rho-kinase inhibitor azaindole-1 has long-lasting erectile activity in the rat. Urology. 2013 Feb;81(2):465.e7-14.

  [3] Dahal BK, Kosanovic D, et al. Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension. Eur Respir J. 2010 Oct;36(4):808-18.