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
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.
