RESUMO
Heteroalicyclic carboxamidines were synthesised and evaluated as inhibitors of nitric oxide synthases. (2R)-2-Pyrrolidinecarboxamidine, in particular, was shown to be a highly potent in vitro (IC(50)=0.12 µM) and selective iNOS inhibitor (>100-fold vs both eNOS and nNOS), with probable binding to the key anchoring glutamate residue and co-ordination to the haem iron.
Assuntos
Amidinas/síntese química , Amidinas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Heme/antagonistas & inibidores , Compostos Heterocíclicos/síntese química , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Prolina/análogos & derivados , Amidinas/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Prolina/síntese química , Prolina/química , Prolina/farmacologiaRESUMO
Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.