ABSTRACT
C5a is a terminal product of the complement cascade that activates and attracts inflammatory cells including granulocytes, mast cells and macrophages via a specific GPCR, the C5a receptor (C5aR). Inhibition of C5a/C5aR interaction has been shown to be efficacious in several animal models of autoimmune diseases, including RA, SLE and asthma. This account reports the discovery of a new class of C5aR antagonists through high-throughput screening. The lead compounds in this series are selective and block C5a binding, C5a-promoted calcium flux in human neutrophils with nanomolar potency.
Subject(s)
Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Sulfonamides/chemistry , Animals , Cell Line , High-Throughput Screening Assays , Humans , Mice , Molecular Conformation , Neutrophils/immunology , Neutrophils/metabolism , Protein Binding , Receptor, Anaphylatoxin C5a/metabolism , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
Our continued effort towards optimization of the pyrazolo[1,5-a]pyrimidine scaffold as B-Raf kinase inhibitors is described. Structure guided design was utilized to introduce kinase hinge region interacting groups in the 2-position of the scaffold. This strategy led to the identification of lead compound 9 with enhanced enzyme and cellular potency, while maintaining good selectivity over a number of kinases.
Subject(s)
Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/chemistry , Pyrimidines/chemistry , Antineoplastic Agents/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Pyrazoles/pharmacology , Pyrimidines/pharmacologyABSTRACT
As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class.
Subject(s)
Benzamides/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Benzamides/chemical synthesis , Benzamides/chemistry , Crystallography, X-Ray , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins B-raf/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
B-Raf kinase plays a critical role in the Raf-MEK-ERK signaling pathway and inhibitors of B-Raf could be used in the treatment of melanomas, colorectal cancer, and other Ras related human cancers. We have identified novel small molecule pyrazolo[1,5-a]pyrimidine derivatives as B-Raf kinase inhibitors. Structure-activity relationship was generated for various regions of the scaffold to improve the biochemical profile.
Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrimidines/chemical synthesis , Cell Line, Tumor , Computer Simulation , Humans , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/metabolism , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity studies of a series of 6-substituted-4-anilino-[1,7]-naphthyridine-3-carbonitriles as inhibitors of Tpl2 kinase are described. The early exploratory work described here may lead to the discovery of compounds with significant therapeutic potential for treating rheumatoid arthritis and other inflammatory diseases.
