ABSTRACT
A new series of novel mast cell tryptase inhibitors is reported, which features the use of an indole structure as the hydrophobic substituent on a m-benzylaminepiperidine template. The best members of this series display good in vitro activity and excellent selectivity against other serine proteases.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Mast Cells/enzymology , Serine Endopeptidases/drug effects , Enzyme Inhibitors/chemistry , Models, Molecular , Structure-Activity Relationship , TryptasesABSTRACT
We exploit the concept of using hydrogen bonds to link multiple ligands for maintaining simultaneous interactions with polyvalent binding sites. This approach is demonstrated by the syntheses and evaluation of pseudo-bivalent ligands as potent inhibitors of human beta-tryptase.
Subject(s)
Drug Design , Enzyme Inhibitors , Serine Endopeptidases/drug effects , Binding Sites , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Hydrogen Bonding , Ligands , Models, Molecular , Molecular Structure , Molecular Weight , Structure-Activity Relationship , TryptasesABSTRACT
In this manuscript, the synthesis and SAR evaluation of a novel pyrazinone class of tryptase inhibitors is described. Chemical optimization of the P1 and P4 groups led to the identification of 7p (K(i)=93 nM) as a potent inhibitor of mast cell tryptase.
