ROCK inhibitor

• CAT Number: I005216
• CAS Number: 867017-68-3
• Molecular Formula: C18H13ClF2N6O
• Molecular Weight: 402.8
• Purity: ≥95%
• Synonyms: 6-chloro-4-N-[3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]pyrimidine-2,4-diamine
• Target: ROCK
• Solubility: 10 mM in DMSO
• Storage: Store at -20°C
• IC50: 0.6 nM(ROCK1); 1.1 nM (ROCK2) [1]
• InChIKey: NRSGWEVTVGZDFC-UHFFFAOYSA-N

ROCK inhibitor(azaindole 1) is a highly potent inhibitor of human ROCK-1 and ROCK-2 isoenzymes with IC50 values of 0.6 and 1.1 nM, respectively.IC50 value: 0.6 nM(ROCK1); 1.1 nM (ROCK2) [1]Target: ROCKin vitro: ROCK inhibitor is a highly potent inhibitor of human ROCK-1 and ROCK-2 isoenzymes with IC50 values of 0.6 and 1.1 nM, respectively. Azaindole 1 inhibited concentration dependently the phenylephrine-induced contraction of rabbit saphenous artery with an IC50 value of 65 nM. In contrast, the ROCK inhibitor Y-27632 relaxed precontracted saphenous artery with an IC50 of 1.5 uM [1].in vivo: In normotensive rats, azaindole 1 also induced a dose dependent and persistent decrease in blood pressure. After oral administration of 3 and 10 mg/kg, mean blood pressure dropped by 20 mm Hg (13%) and 41 mm Hg (40%), respectively. The effect lasted approximately 10 h after oral application of 3 mg/kg and more than 24 h after 10 mg/kg. A slight and transient increase of heart rate was only observed in rats treated with the highest dose of azaindole 1, 10 mg/kg [1].

Reference

[1]. Kast, R.; Schirok, H.; Figueroa-Perez, S.; Mittendorf, J.; Gnoth, M. J.; Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase. British Journal of Pharmacology (2007), 152(7), 1070-1080.
Abstract
BACKGROUND AND PURPOSE: Rho-kinase (ROCK) has been implicated in the pathophysiology of altered vasoregulation leading to hypertension. Here we describe the pharmacological characterization of a potent, highly selective and orally active ROCK inhibitor, the derivative of a class of azaindoles, azaindole 1 (6-chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-phenyl}pyrimidine-2,4-diamine). EXPERIMENTAL APPROACH: Pharmacological characterization of azaindole 1 was performed with human recombinant ROCK in vitro. Vasodilator activity was determined using isolated vessels in vitro and different animal models in vivo. KEY RESULTS: This compound inhibited the ROCK-1 and ROCK-2 isoenzymes with IC50 s of 0.6 and 1.1 nM in an ATP-competitive manner. Although ATP-competitive, azaindole 1 was inactive against 89 kinases (IC50>10 microM) and showed only weak activity against an additional 21 different kinases (IC50=1-10 microM). Only the kinases TRK und FLT3 were inhibited by azaindole 1 in the sub-micromolar range, albeit with IC50 values of 252 and 303 nM, respectively. In vivo, azaindole 1 lowered blood pressure dose-dependently after i.v. administration in anaesthetized normotensive rats. In conscious normotensive and spontaneously hypertensive rats azaindole 1 induced a dose-dependent decrease in blood pressure after oral administration without inducing a significant reflex increase in heart rate. In anaesthetized dogs, azaindole 1 induced vasodilatation with a moderately elevated heart rate. CONCLUSIONS AND IMPLICATIONS: Azaindole 1 is representative of a new class of selective and potent ROCK inhibitors and is a valuable tool for the elucidation of the role of ROCK in the cardiovascular system.