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Cardiovascular effects of a novel potent and highly selective azaindole‐based inhibitor of Rho‐kinase
Author(s) -
Kast R,
Schirok H,
FigueroaPérez S,
Mittendorf J,
Gnoth M J,
Apeler H,
Lenz J,
Franz J K,
Knorr A,
Hütter J,
Lobell M,
Zimmermann K,
Münter K,
Augstein K H,
Ehmke H,
Stasch J P
Publication year - 2007
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707484
Subject(s) - in vivo , kinase , pharmacology , vasodilation , chemistry , in vitro , blood pressure , pyrimidine , heart rate , protein kinase a , enzyme , biochemistry , medicine , biology , microbiology and biotechnology
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