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Design and Synthesis of Potent and Selective Azaindole‐Based Rho Kinase (ROCK) Inhibitors
Author(s) -
Schirok Hartmut,
Kast Raimund,
FigueroaPérez Santiago,
Bennabi Samir,
Gnoth Mark J.,
Feurer Achim,
Heckroth Heike,
Thutewohl Michael,
Paulsen Holger,
Knorr Andreas,
Hütter Joachim,
Lobell Mario,
Münter Klaus,
Geiß Volker,
Ehmke Heimo,
Lang Dieter,
Radtke Martin,
Mittendorf Joachim,
Stasch JohannesPeter
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800211
Subject(s) - moiety , chemistry , kinase , in vivo , bicyclic molecule , rho associated protein kinase , structure–activity relationship , stereochemistry , combinatorial chemistry , pharmacology , biochemistry , in vitro , biology , microbiology and biotechnology
Rho kinase plays a pivotal role in several cellular processes such as vasoregulation, making it a suitable target for the treatment of hypertension and related disorders. We discovered a new compound class of Rho kinase (ROCK) inhibitors containing a 7‐azaindole hinge‐binding scaffold tethered to an aminopyrimidine core. Herein we describe the structure–activity relationships elucidated through biochemical and functional assays. The introduction of suitable substituents at the 3‐position of the bicyclic moiety led to an increase in activity, which was required to design compounds with favorable pharmacokinetic profile. Azaindole 32 was identified as a highly selective and orally available ROCK inhibitor able to cause a sustained blood pressure reduction in vivo.