ABSTRACT
5-Aryl-4-carboxamide-1,3-oxazoles are a novel, potent and selective series of GSK-3 inhibitors. The optimization of the series to yield compounds with cell activity and brain permeability is described.
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Oxazoles/chemistry , Oxazoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Animals , Bipolar Disorder/drug therapy , Brain/metabolism , Glycogen Synthase Kinase 3/metabolism , Humans , Models, Molecular , Oxazoles/chemical synthesis , Oxazoles/pharmacokinetics , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
The discovery of a novel series of 2-(4-pyridyl)thienopyridinone GSK-3ß inhibitors is reported. X-ray crystallography reveals its binding mode and enables rationalization of the SAR. The initial optimization of the template for improved cellular activity and predicted CNS penetration is also presented.
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridones/pharmacology , Thiophenes/pharmacology , Cell Line , Central Nervous System/drug effects , Central Nervous System/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Discovery , Glycogen Synthase Kinase 3 beta , Humans , Models, Molecular , Molecular Structure , Permeability/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridones/chemical synthesis , Pyridones/chemistry , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistryABSTRACT
The discovery and hit-to-lead exploration of a novel series of selective IKK-ß kinase inhibitors is described. The initial lead fragment 3 was identified by pharmacophore-directed virtual screening. Homology model-driven SAR exploration of the template led to potent inhibitors, such as 12, which demonstrate efficacy in cellular assays and possess encouraging developability profiles.
Subject(s)
Amides/chemistry , I-kappa B Kinase/antagonists & inhibitors , Indoles/chemistry , Protein Kinase Inhibitors/chemistry , Administration, Oral , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Binding Sites , Computer Simulation , Drug Evaluation, Preclinical , Humans , I-kappa B Kinase/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
The identification and progression of a potent and selective series of isoquinoline inhibitors of IkappaB kinase-beta (IKK-beta) are described. Hit-generation chemistry based on IKK-beta active-site knowledge yielded a weakly potent but tractable chemotype that was rapidly progressed into a series with robust enzyme and cellular activity and significant selectivity over IKK-alpha.
Subject(s)
Drug Discovery , I-kappa B Kinase/antagonists & inhibitors , Isoquinolines/chemistry , Isoquinolines/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Humans , I-kappa B Kinase/chemistry , I-kappa B Kinase/metabolism , Inhibitory Concentration 50 , Isoquinolines/metabolism , Models, Molecular , Molecular Conformation , Protein Kinase Inhibitors/metabolismABSTRACT
The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity.
Subject(s)
Chemistry, Pharmaceutical/methods , I-kappa B Kinase/antagonists & inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Adenosine Triphosphate/chemistry , Binding Sites , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Molecular Structure , Protein Binding , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
A potent and selective series of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta is described. The most potent compounds are 8h, 8r and 8v, with IKK-beta inhibitory potencies of pIC(50) 7.0, 6.8 and 6.8, respectively. The series has excellent selectivity, both within the IKK family over IKK-epsilon, and across a wide variety of kinase assays. The potency of 8h in the IKK-beta enzyme assay translates to significant cellular activity (pIC(50) 5.7-6.1) in assays of functional and mechanistic relevance.
Subject(s)
Benzamides/pharmacology , Enzyme Inhibitors/pharmacology , I-kappa B Kinase/antagonists & inhibitors , Benzamides/chemistry , Enzyme Inhibitors/chemistry , Hydrogen Bonding , Models, MolecularABSTRACT
The identification and hit-to-lead exploration of a novel, potent and selective series of substituted benzimidazole-thiophene carbonitrile inhibitors of IKK-epsilon kinase is described. Compound 12e was identified with an IKK-epsilon enzyme potency of pIC(50) 7.4, and has a highly encouraging wider selectivity profile, including selectivity within the IKK kinase family.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , I-kappa B Kinase/antagonists & inhibitors , Nitriles/chemical synthesis , Nitriles/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Hydrogen Bonding , Kinetics , Models, Molecular , Thiophenes/chemistry , X-Ray DiffractionABSTRACT
The discovery, synthesis, potential binding mode, and in vitro kinase profile of several pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidines as potent kinase inhibitors are discussed.