RESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Mastócitos/enzimologia , Serina Endopeptidases/efeitos dos fármacos , Inibidores Enzimáticos/química , Modelos Moleculares , Relação Estrutura-Atividade , TriptasesRESUMO
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.
Assuntos
Pirazinas/síntese química , Serina Endopeptidases/efeitos dos fármacos , Inibidores de Serina Proteinase/síntese química , Pirazinas/farmacologia , Serina Endopeptidases/química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , TriptasesRESUMO
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.