ABSTRACT
A series of SYK inhibitors based on the phenylamino pyrimidine thiazole lead 4 were prepared and evaluated for biological activity. Lead optimization provided compounds with nanomolar K(i)'s against SYK and potent inhibition in mast cell degranulation assays.
Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Spleen/enzymology , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Animals , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Drug Design , Mast Cells/drug effects , Microsomes, Liver/drug effects , Molecular Conformation , Molecular Structure , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Rats , Structure-Activity Relationship , Syk Kinase , Thiazoles/chemistryABSTRACT
The alpha-ketoamide warhead (e.g., 15) was found to be a practical replacement for aliphatic aldehydes in a series of HCV NS3.4A protease inhibitors. Structure-activity relationships and prime side optimization are discussed.
Subject(s)
Hepacivirus/enzymology , Macrocyclic Compounds , Quinolines , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Carbamates/chemistry , Carbamates/metabolism , Hepacivirus/drug effects , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/metabolism , Viral Nonstructural Proteins/metabolismABSTRACT
Tetrapeptide-based peptidomimetic compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease without the need of a charged functionality. An aldehyde is used as a prototype reversible electrophilic warhead. The SAR of the P1 and P2 inhibitor positions is discussed.
