ABSTRACT
The discovery of a sulphonamide by-product with VLA-4 antagonistic activity led to a series of potent, small molecule VLA-4 antagonists. Synthesis, SAR and in vivo evaluation of the selected compound will be presented.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Animals , Asthma/drug therapy , Asthma/pathology , Cell Adhesion/drug effects , Cell Line , Cell Movement/drug effects , Eosinophils/drug effects , Female , Half-Life , Indicators and Reagents , Leukocytes/drug effects , Macaca fascicularis , Mice , Mice, Inbred BALB C , Ovalbumin/immunology , Structure-Activity RelationshipABSTRACT
Selective inhibitors of protein tyrosine phosphatases (PTPases) are of great interest as therapeutic agents and research tools. Several phenylalanine derivatives (1, 2) designed as phosphotyrosine mimetics or irreversible active site inhibitors were successfully synthesized, then incorporated into a combinatorial library based on a peptidomimetic beta-strand template.
Subject(s)
Phosphotyrosine/analogs & derivatives , Phosphotyrosine/chemical synthesis , Biomimetic Materials/chemical synthesis , Combinatorial Chemistry Techniques/methods , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Peptide Library , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacology , Protein Structure, Secondary , Protein Tyrosine Phosphatases/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
A novel alpha-addition of propiolates to urazoles followed by Michael addition of a variety of nucleophiles has been developed for rapid production and optimization of peptidomimetic drug leads. This technology has produced a number of highly potent and selective inhibitors of the serine protease, thrombin.