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

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‐N ⁴‐{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 1was 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 1was inactive against 89 kinases (IC₅₀>10 μM) and showed only weak activity against an additional 21 different kinases (IC₅₀=1 ‐ 10 μM). Only the kinases TRK und FLT3 were inhibited by azaindole 1in the sub‐micromolar range, albeit with IC₅₀ values of 252 and 303 nM, respectively. In vivo, azaindole 1lowered blood pressure dose‐dependently after i.v. administration in anaesthetized normotensive rats. In conscious normotensive and spontaneously hypertensive rats azaindole 1induced a dose‐dependent decrease in blood pressure after oral administration without inducing a significant reflex increase in heart rate. In anaesthetized dogs, azaindole 1induced vasodilatation with a moderately elevated heart rate. Conclusions and implications: Azaindole 1is 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