Orally active GPIIb/IIIa antagonists: Synthesis and biological activities of masked amidines as prodrugs of 2-[(3S)-4-[(2S)-2-(4-amidinobenzoylanlino)-3-(4-methoxyphenyl)propanoyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiperazinyl]acetic acid

To improve the in vivo potency of the potent GPIIb/IIIa antagonist 2-[(3S)- 4-[(2S)-2-(4-amidinobenzoylamino)-3-(4-methoxyphenyl) propanoyl]-3-(2-metho xy-2-oxoethyl)-2-oxopiperazinyl]acetic acid (4), the amidino group was conv erted to an oxadiazole ring, thiadiazole ring or substituted amidoxime grou p. These groups,were expected to be metabolized to an amidino group in vivo . The compounds synthesized were evaluated for their potency to inhibit the ex vivo adenosine 5'-diphosphate (ADP)-induced aggregation of guinea pig p latelets. Among the compounds examined, the methoxycarbonyloxyamidine 8a ex hibited the most potent ex vivo inhibitory activity with a fast onset and p rolonged duration of action after oral administration.