ABSTRACT
This Letter details the synthesis and evaluation of imidazo[4,5-b]pyridines as inhibitors of B-Raf kinase. These compounds bind in a DFG-in, αC-helix out conformation of B-Raf, which is a binding mode associated with significant kinase selectivity. Structure-activity relationship studies involved optimization of the ATP-cleft binding region of these molecules, and led to compound 23, an inhibitor with excellent enzyme/cell potency, and kinase selectivity.
Subject(s)
Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Purines/chemistry , Purines/pharmacology , Animals , Caco-2 Cells , Drug Design , Humans , Mice , Molecular Docking Simulation , Proto-Oncogene Proteins B-raf/chemistry , Proto-Oncogene Proteins B-raf/metabolism , Purines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
The synthesis and biological evaluation of non-oxime pyrazole based B-Raf inhibitors is reported. Several oxime replacements have been prepared and have shown excellent enzyme activity. Further optimization of fused pyrazole 2a led to compound 38, a selective and potent B-Raf inhibitor.
Subject(s)
Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Inhibitory Concentration 50 , Mice , Molecular Structure , Oximes/chemistry , Pyrazoles/chemistryABSTRACT
A series of racemic and chiral, nonracemic lactams that display high binding affinities, functional chemotaxis antagonism, and selectivity toward CCR4 are described. Compound 41, which provides reasonably high blood levels in mice when dosed intraperitoneally, was identified as a useful pharmacological tool to explore the role of CCR4 antagonism in animal models of allergic disease.
Subject(s)
Lactams/chemistry , Lactams/pharmacokinetics , Receptors, Chemokine/antagonists & inhibitors , Animals , Binding Sites , Binding, Competitive/drug effects , Disease Models, Animal , Drug Evaluation, Preclinical , Hypersensitivity/drug therapy , Lactams/chemical synthesis , Mice , Molecular Structure , Receptors, CCR4 , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Substituted thiazolidinones were identified as CCR4 antagonists from high throughput screening. Subsequent lead optimization efforts resulted in defined structure-activity relationships and the identification of potent antagonists (compounds 90 and 91) that inhibited the chemotaxis of Th2 T-cells in vitro.
Subject(s)
Receptors, Chemokine/antagonists & inhibitors , Thiazolidinediones/chemistry , Animals , Mice , Protein Binding/physiology , Receptors, CCR4 , Receptors, Chemokine/metabolism , Structure-Activity Relationship , Thiazolidinediones/metabolism , Thiazolidinediones/pharmacologyABSTRACT
The past several years has seen research increasingly focused around the inhibition of tryptase, a mast cell protease implicated in a myriad of pro-inflammatory responses. Although few compounds have reached the clinic, several monobasic and multibasic small molecules have emerged as promising candidates as a treatment for asthma and other allergic and inflammatory disorders. This summary reviews recent patent activity of tryptase inhibitors and briefly outlines recent tryptase inhibitor literature and clinical updates.
