Biomaterial Database

Design and synthesis of potent and selective azaindole-based Rho kinase (ROCK) inhibitors. 2008

Hartmut Schirok, and Raimund Kast, and Santiago Figueroa-Pérez, and Samir Bennabi, and Mark J Gnoth, and Achim Feurer, and Heike Heckroth, and Michael Thutewohl, and Holger Paulsen, and Andreas Knorr, and Joachim Hütter, and Mario Lobell, and Klaus Münter, and Volker Geiss, and Heimo Ehmke, and Dieter Lang, and Martin Radtke, and Joachim Mittendorf, and Johannes-Peter Stasch

Bayer HealthCare AG, Medicinal Chemistry, 42096 Wuppertal, Germany. hartmut.schirok@bayerhealthcare.com

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.

UI	MeSH Term	Description	Entries
D007211	Indoles	Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D008958	Models, Molecular	Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.	Molecular Models,Model, Molecular,Molecular Model
D011743	Pyrimidines	A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015195	Drug Design	The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis.	Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D017208	Rats, Wistar	A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain.	Wistar Rat,Rat, Wistar,Wistar Rats
D051381	Rats	The common name for the genus Rattus.	Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D054460	rho-Associated Kinases	A group of intracellular-signaling serine threonine kinases that bind to RHO GTP-BINDING PROTEINS. They were originally found to mediate the effects of rhoA GTP-BINDING PROTEIN on the formation of STRESS FIBERS and FOCAL ADHESIONS. Rho-associated kinases have specificity for a variety of substrates including MYOSIN-LIGHT-CHAIN PHOSPHATASE and LIM KINASES.	rho-Associated Kinase,ROCK Protein Kinases,ROCK-I Protein Kinase,ROCK-II Protein Kinase,ROK Kinase,p160 rhoA-Binding Kinase ROKalpha,p160ROCK,rho-Associated Coiled-Coil Containing Protein Kinase 1,rho-Associated Coiled-Coil Containing Protein Kinase 2,rho-Associated Coiled-Coil Kinase,rho-Associated Kinase 1,rho-Associated Kinase 2,rho-Associated Kinase alpha,rho-Associated Kinase beta,rho-Associated Protein Kinase alpha,rho-Associated Protein Kinase beta,rho-Kinase,Coiled-Coil Kinase, rho-Associated,Protein Kinases, ROCK,ROCK I Protein Kinase,ROCK II Protein Kinase,p160 rhoA Binding Kinase ROKalpha,rho Associated Coiled Coil Containing Protein Kinase 1,rho Associated Coiled Coil Containing Protein Kinase 2,rho Associated Coiled Coil Kinase,rho Associated Kinase,rho Associated Kinase 1,rho Associated Kinase 2,rho Associated Kinase alpha,rho Associated Kinase beta,rho Associated Kinases,rho Associated Protein Kinase alpha,rho Associated Protein Kinase beta,rho Kinase