Cardiovascular effects of a novel potent and highly selective azaindole‐based inhibitor of Rho‐kinase

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‐ N 4 ‐{3,5‐difluoro‐4‐[(3‐methyl‐1 H ‐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 IC 50  s of 0.6 and 1.1 nM in an ATP‐competitive manner. Although ATP‐competitive, azaindole 1 was inactive against 89 kinases (IC 50 >10 μM) and showed only weak activity against an additional 21 different kinases (IC 50 =1 ‐ 10 μM). Only the kinases TRK und FLT3 were inhibited by azaindole 1 in the sub‐micromolar range, albeit with IC 50 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. British Journal of Pharmacology (2007) 152 , 1070–1080; doi: 10.1038/sj.bjp.0707484 ; published online 15 October 2007