ABSTRACT
A series of pyrazolo[1,5-a]pyridine derivatives was designed and synthesized as novel potent p38 kinase inhibitors. Our approaches towards improving in vitro metabolism and in vivo pharmacokinetic properties of the series are described.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Pyridines/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Area Under Curve , Dogs , Drug Design , Humans , Inhibitory Concentration 50 , Leukocytes, Mononuclear/drug effects , MAP Kinase Signaling System , Pyridines/pharmacokinetics , Rats , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
[reaction: see text] A convergent synthesis of substituted pyrazolo[1,5-a]pyridines has been achieved either via a regioselective [3 + 2] cycloaddition of N-aminopyridines with alkynes or by thermal cyclization of disubstituted azirines. Subsequent palladium-catalyzed introduction of pyridines or de novo synthesis of pyrimidines affords inhibitors of p38 kinase.
Subject(s)
Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , Pyridines/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Crystallography, X-Ray , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Kinases/drug effects , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Humans , Hydrogen Bonding , Molecular Structure , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Structure, Tertiary , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of imidazo[4,5-c]pyridines bearing a 1,2,5-oxadiazol-3-ylamine functionality has been developed. These are potent inhibitors of mitogen and stress-activated protein kinase-1.
