RESUMO
The discovery of a highly potent and selective tissue factor/factor VIIa inhibitor is described. Upon oral administration of its double prodrug in the guinea pig, a dose-dependent antithrombotic effect is observed in an established model of arterial thrombosis without prolonging bleeding time. The pharmacodynamic properties of this selective inhibitor are compared to the behaviour of a mixed factor VIIa/factor Xa inhibitor.
Assuntos
Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Inibidores dos Fatores de Coagulação Sanguínea/síntese química , Inibidores dos Fatores de Coagulação Sanguínea/farmacologia , Fator VIIa/antagonistas & inibidores , Tromboplastina/antagonistas & inibidores , Administração Oral , Animais , Tempo de Sangramento , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Cobaias , Humanos , Modelos Moleculares , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Trombose/tratamento farmacológico , Trombose/prevenção & controleRESUMO
We describe the structure-based design and synthesis of highly potent, orally bioavailable tissue factor/factor VIIa inhibitors which interfere with the coagulation cascade by selective inhibition of the extrinsic pathway.
Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Fator VIIa/antagonistas & inibidores , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Tromboplastina/antagonistas & inibidores , Administração Oral , Animais , Anticoagulantes/síntese química , Disponibilidade Biológica , Cristalografia por Raios X , Desenho de Fármacos , Glicina/análogos & derivados , Glicina/química , Humanos , Estrutura Molecular , Ratos , Inibidores de Serina Proteinase/síntese químicaRESUMO
Proof of concept experiments have shown that tissue factor/factor VIIa inhibitors have antithrombotic activity without enhancing bleeding propensity. Starting from lead compounds generated by a biased combinatorial approach, phenylglycine amide tissue factor/factor VIIa inhibitors with low nanomolar affinity and good selectivity against other serine proteases of the coagulation cascade were designed, using the guidance of X-ray structural analysis and molecular modelling.
Assuntos
Fator VIIa/antagonistas & inibidores , Fibrinolíticos/síntese química , Glicina/análogos & derivados , Glicina/síntese química , Glicina/farmacologia , Tromboplastina/antagonistas & inibidores , Desenho de Fármacos , Fibrinolíticos/farmacologia , Humanos , Cinética , Modelos Moleculares , Estrutura Molecular , Inibidores de Serina Proteinase/síntese química , Relação Estrutura-AtividadeRESUMO
The prediction of a ligand binding constant requires generating three-dimensional structures of the complex concerned and reliably scoring these structures. Here, the scoring problem is investigated by examining benzamidine-like inhibitors of trypsin, a system for which errors in the structures are small. Precise and consistent binding free energies for the inhibitors are determined experimentally for this test system. To examine possible improvement of scoring methods, we test the suitability of continuum electrostatics to account for solvation effects and use an ideal-gas entropy correction to account for the changes in the degrees of freedom of the ligand. The small observed root-mean-square deviation of 0.55 kcal/mol of the calculated relative to the experimental values indicates that the essentials of the binding process have been captured. Even though all six ligands make the same salt bridge and H-bonds to the protein, the electrostatic contribution varies among the ligands by as much as 2 kcal/mol. Moreover, although the ligands are rigid and similar in size, the entropic terms also significantly affect the relative binding affinities (by up to 2.7 kcal/mol). The present approach to solvation and entropy may allow the ranking of the ligands to be considerably improved at a cost that makes the method applicable to the optimization of lead compounds or to the screening of small collections of ligands.