RESUMO
The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.
Assuntos
Inibidores do Fator Xa , Pirrolidinas/química , Pirrolidinas/farmacologia , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Desenho de Fármacos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
The discovery and evaluation of potent and long-acting oral sulfonamidopyrrolidin-2-one factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs are described. Unexpected selectivity issues versus tissue plasminogen activator in the former series were addressed in the later, delivering a robust candidate for progression towards clinical studies.
Assuntos
Benzazepinas/síntese química , Inibidores do Fator Xa , Inibidores de Serina Proteinase/química , Tetra-Hidroisoquinolinas/química , Administração Oral , Animais , Benzazepinas/administração & dosagem , Benzazepinas/farmacologia , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Estrutura Molecular , Ratos , Inibidores de Serina Proteinase/administração & dosagem , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/farmacologiaRESUMO
Optimisation of a series of oxazole diketopiperazines has led to the discovery of a very potent and selective oxytocin antagonist GSK221149A. GSK221149A has been shown to inhibit oxytocin-induced uterine contractions in the anaesthetised rat.