RESUMO
A novel series of pyrrolidine-1,2-dicarboxamides was discovered as factor Xa inhibitors using structure-based drug design. This series consisted of a neutral 4-chlorophenylurea P1, a biphenylsulfonamide P4 and a D-proline scaffold (1, IC(50) = 18 nM). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC(50) = 0.38 nM), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.
Assuntos
Antitrombina III/química , Química Farmacêutica/métodos , Ácido Pirrolidonocarboxílico/farmacologia , Administração Oral , Animais , Antitrombina III/farmacologia , Cristalização , Cães , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Ligação Proteica , Ácido Pirrolidonocarboxílico/química , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.
Assuntos
Antitrombina III/síntese química , Antitrombina III/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Anticoagulantes/síntese química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Antitrombina III/farmacocinética , Cristalografia por Raios X , Cães , Humanos , Masculino , Piridonas/farmacocinética , Pirrolidinas/farmacocinética , Coelhos , Ratos , Relação Estrutura-AtividadeRESUMO
Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.
Assuntos
Inibidores do Fator Xa , Fator Xa/química , Glicina/análogos & derivados , Glicina/química , Inibidores de Serina Proteinase/química , Cristalografia por Raios X , Humanos , Estrutura Molecular , Conformação ProteicaRESUMO
We have found that both enantiomeric configurations of the 6-alkoxymethyl-1-aryl-2-piperazinone scaffold display equipotent renin inhibition activity and similar SAR patterns. This enantiomeric flexibility is in contrast to a previously reported 3-alkoxymethyl-4-arylpiperidine scaffold.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Renina/antagonistas & inibidores , Sítios de Ligação , Inibidores Enzimáticos/química , Indicadores e Reagentes , Conformação Molecular , Estrutura Molecular , Piperazinas/química , Conformação Proteica , Renina/química , EstereoisomerismoRESUMO
Inhibition of renin enzymatic activity by a series of ketopiperazine-based compounds containing a C6 benzyloxymethyl substituent correlated with a +(pi+sigma) effect. A 3-pyridinyloxymethyl substituent was also found to be equipotent as higher molecular weight analogs, and exhibited decreased CYP3A4 inhibition levels and improved pharmacokinetic properties.
Assuntos
Piperazinas/síntese química , Renina/antagonistas & inibidores , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Células CACO-2 , Permeabilidade da Membrana Celular , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Éter , Humanos , Concentração Inibidora 50 , Piperazina , Piperazinas/farmacocinética , Piperazinas/farmacologia , Solubilidade , Relação Estrutura-AtividadeRESUMO
Ketopiperazine 2 was designed from a previously published analog. Compound 2 was shown to be a novel, potent inhibitor of renin that, when administered orally, lowered blood pressure in a hypertensive double transgenic (human renin and angiotensinogen) mouse model. Compound 2 was further optimized to sub-nanomolar potency by designing an analog that addressed the S3 sub-pocket of the renin enzyme (16).