Design, synthesis, bioconversion, and pharmacokinetics evaluation of new ester prodrugs of olmesartan

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, Cmax and AUClast 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.

Synthesis of new ester prodrugs of olmesartan is described. Their in vitro stabilities in simulated gastric juice, rat plasma, and rat liver microsomes, in addition to in vivo pharmacokinetic parameters were evaluated.Figure optionsDownload as PowerPoint slideHighlights
► New ester prodrugs of olmesartan were synthesized.
► Their in vitro stabilities and in vivo pharmacokinetic parameters were evaluated.
► Compounds 13 and 14 showed high stability in simulated gastric juice.
► 13 and 14 were metabolized to olmesartan in rat liver microsomes and plasma in vitro.
► Cmax and AUClast were significantly increased in case of compounds 13 and 14.