RESUMO
Thrombin plays a key role in the control of thrombus formation, for which reason its inhibition has become a target for new antithrombotics. Important issues in the profile of the ideal thrombin inhibitor are: potency, selectivity, oral bioavailability, half-life in the circulatory system and safety. Although many potent direct inhibitors of thrombin have been discovered, most of these inhibitors lack sufficient oral bioavailability. This is often associated with the presence of highly basic functionalities such as guanidine or amidine. These basic functionalities in the P1 moiety are preferred by thrombin and are present in the first generation of thrombin inhibitors. Recently, several orally active direct thrombin inhibitors have been disclosed. Most of these inhibitors originate from leads of the first generation. Two major optimization strategies could be identified to further improve these leads: A: maintain the highly basic P1 moiety and compensate its negative effects, and B: reduce the basicity of the P1 moiety and compensate for the decrease in inhibitory activity. The progress made using these strategies is evaluated. In addition, screening large sets of compounds yielded new structures that provide useful starting points for optimization. The optimization strategy used to convert leads from screening into potent orally active thrombin inhibitors is also be evaluated.
Assuntos
Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Trombina/antagonistas & inibidores , Administração Oral , Amidinas/farmacologia , Animais , Disponibilidade Biológica , Ensaios Clínicos como Assunto , Fibrinolíticos/toxicidade , Guanidina/farmacologia , Humanos , Sensibilidade e Especificidade , Relação Estrutura-Atividade , Trombina/químicaRESUMO
Replacement of the highly basic benzamidine moiety with moderate basic amino-bicycloaryl moieties in a series of thrombin inhibitors related to NAPAMP provided potent enzyme inhibition and significant improvements in membrane transport and oral bioavailability.
Assuntos
Antitrombinas/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Trombina/antagonistas & inibidores , Administração Oral , Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Antitrombinas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células CACO-2 , Permeabilidade da Membrana Celular , Desenho de Fármacos , Humanos , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/farmacologia , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologiaRESUMO
Replacement of the highly basic benzamidine moiety of NAPAP by the moderately basic 1-aminoisoquinoline moiety resulted in thrombin inhibitors with improved selectivity towards trypsin and enhanced Caco-2 cell permeability.
