RESUMO
Synthesis of new ester prodrugs of olmesartan is described. Their in vitro stabilities in simulated gastric juice, rat plasma, and rat liver microsomes were tested. And the pharmacokinetic parameters for olmesartan after their oral administration were also estimated and compared with those in case of olmesartan medoxomil. Compounds 13 and 14 demonstrated high stability in simulated gastric juice and were rapidly metabolized to olmesartan in rat liver microsomes and rat plasma in vitro. In addition, C(max) and AUC(last) parameters were significantly increased in case of compounds 13 and 14 compared with olmesartan medoxomil. These results indicate that compounds 13 and 14 with cyclohexylcarboxyethyl and adamantylcarboxymethyl promoieties, respectively, are promising prodrugs of olmesartan with markedly increased oral bioavailability.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Desenho de Fármacos , Imidazóis/química , Imidazóis/farmacocinética , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Tetrazóis/química , Tetrazóis/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Animais , Área Sob a Curva , Cromatografia Líquida , Avaliação Pré-Clínica de Medicamentos , Ésteres , Suco Gástrico/metabolismo , Meia-Vida , Imidazóis/síntese química , Espectroscopia de Ressonância Magnética , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Pró-Fármacos/síntese química , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Tetrazóis/síntese químicaRESUMO
Synthesis of novel amides and esters prodrugs of olmesartan is described. Their in vitro stability in rat plasma was tested. The results showed that the ester derivative IIa with n-octyl substituted dioxolone moiety was rapidly converted into olmesartan within 30 min. The pharmacokinetic parameters of IIa were studied and compared with those of olmesartan medoxomil. Compound IIa is proposed to be a promising prodrug of olmesartan.
