RESUMO
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Inibidores do Fator Xa , Pirrolidinonas/química , Inibidores de Serina Proteinase/química , Animais , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Masculino , Modelos Moleculares , Pirrolidinonas/farmacocinética , Pirrolidinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.
Assuntos
Inibidores do Fator Xa , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Animais , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Desenho de Fármacos , Masculino , Modelos Moleculares , Pirrolidinonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaRESUMO
Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.
Assuntos
Anticoagulantes/síntese química , Inibidores do Fator Xa , Fator Xa/química , Morfolinas/síntese química , Pirrolidinas/síntese química , Sulfonamidas/síntese química , Animais , Anticoagulantes/química , Anticoagulantes/farmacologia , Cristalografia por Raios X , Cães , Feminino , Humanos , Ligantes , Masculino , Modelos Moleculares , Estrutura Molecular , Morfolinas/química , Morfolinas/farmacologia , Ligação Proteica , Tempo de Protrombina , Pirrolidinas/química , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Albumina Sérica/química , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/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.
Assuntos
Alanina/química , Amidas/química , Antitrombina III/síntese química , Antitrombina III/farmacologia , Desenho de Fármacos , Pirróis/química , Anticoagulantes/síntese química , Anticoagulantes/química , Anticoagulantes/metabolismo , Anticoagulantes/farmacologia , Antitrombina III/química , Antitrombina III/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Fator Xa/química , Fator Xa/metabolismo , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.