期刊
CHEMMEDCHEM
卷 3, 期 12, 页码 1893-1904出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.200800211
关键词
structure-activity relationships; 7-azaindole inhibitors; Rho kinase; vasorelaxation
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.
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