ChemMedChem, 2008-12-15, Vol.3 (12), p.1893-1904
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.
A new compound class of Rho kinase (ROCK) inhibitors containing a 7‐azaindole hinge‐binding moiety was discovered. The introduction of substituents at the 3‐position of the bicyclic ring system led to a significant increase in activity and permitted the design of compounds with a favorable pharmacokinetic profile. The ROCK inhibitors are orally bioavailable and mediate a sustained blood pressure lowering effect in vivo.
7-azaindole ; Animals ; Drug Design ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - pharmacology ; inhibitors ; Inhibitory Concentration 50 ; Models, Molecular ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Rats ; Rats, Wistar ; Rho kinase ; rho-Associated Kinases - antagonists & inhibitors ; rho-Associated Kinases - pharmacology ; Structure-Activity Relationship ; structure-activity relationships ; vasorelaxation
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