Klaus Münter

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

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).

Design and Synthesis of Potent and Selective Azaindole‐Based Rho Kinase (ROCK) Inhibitors

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.