title: Design and synthesis of potent and selective azaindole-based Rho kinase (ROCK) inhibitors.
abstract: 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.
authors.affiliation: Bayer HealthCare AG, Medicinal Chemistry, 42096 Wuppertal, Germany. hartmut.schirok@bayerhealthcare.com
authors.forename: Hartmut
authors.initials: H
authors.lastname: Schirok
authors.forename: Raimund
authors.initials: R
authors.lastname: Kast
authors.forename: Santiago
authors.initials: S
authors.lastname: Figueroa-Pérez
authors.forename: Samir
authors.initials: S
authors.lastname: Bennabi
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Gnoth
authors.forename: Achim
authors.initials: A
authors.lastname: Feurer
authors.forename: Heike
authors.initials: H
authors.lastname: Heckroth
authors.forename: Michael
authors.initials: M
authors.lastname: Thutewohl
authors.forename: Holger
authors.initials: H
authors.lastname: Paulsen
authors.forename: Andreas
authors.initials: A
authors.lastname: Knorr
authors.forename: Joachim
authors.initials: J
authors.lastname: Hütter
authors.forename: Mario
authors.initials: M
authors.lastname: Lobell
authors.forename: Klaus
authors.initials: K
authors.lastname: Münter
authors.forename: Volker
authors.initials: V
authors.lastname: Geiss
authors.forename: Heimo
authors.initials: H
authors.lastname: Ehmke
authors.forename: Dieter
authors.initials: D
authors.lastname: Lang
authors.forename: Martin
authors.initials: M
authors.lastname: Radtke
authors.forename: Joachim
authors.initials: J
authors.lastname: Mittendorf
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D011743:Pyrimidines; D054460:rho-Associated Kinases