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.
Schirok
Hartmut
H
Bayer HealthCare AG, Medicinal Chemistry, 42096 Wuppertal, Germany. hartmut.schirok@bayerhealthcare.com
Kast
Raimund
R
Figueroa-Pérez
Santiago
S
Bennabi
Samir
S
Gnoth
Mark J
MJ
Feurer
Achim
A
Heckroth
Heike
H
Thutewohl
Michael
M
Paulsen
Holger
H
Knorr
Andreas
A
Hütter
Joachim
J
Lobell
Mario
M
Münter
Klaus
K
Geiss
Volker
V
Ehmke
Heimo
H
Lang
Dieter
D
Radtke
Martin
M
Mittendorf
Joachim
J
Stasch
Johannes-Peter
JP
D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007211:Indoles; D011743:Pyrimidines; D054460:rho-Associated Kinases