Orally Active GPIIb/IIIa Antagonists: Synthesis and Biological Activities of Masked Amidines as Prodrugs of 2-[(3S)-4-[(2S)-2-(4-Amidinobenzoylamino)-3-(4-methoxyphenyl)propanoyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiperazinyl]acetic Acid

Shuji KITAMURA; Hideto FUKUSHI; Toshio MIYAWAKI; Masaki KAWAMURA; Zen-ichi TERASHITA; Takehiko NAKA

doi:10.1248/cpb.49.268

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Orally Active GPIIb/IIIa Antagonists: Synthesis and Biological Activities of Masked Amidines as Prodrugs of 2-[(3S)-4-[(2S)-2-(4-Amidinobenzoylamino)-3-(4-methoxyphenyl)propanoyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiperazinyl]acetic Acid

Shuji KITAMURA, Hideto FUKUSHI, Toshio MIYAWAKI, Masaki KAWAMURA, Zen-ichi TERASHITA, Takehiko NAKA

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Keywords: GPIIb/IIIa antagonist, antiplatelet effect, masked amidine, prodrugs for arylamidines

JOURNAL FREE ACCESS

2001 Volume 49 Issue 3 Pages 268-277

DOI https://doi.org/10.1248/cpb.49.268

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Abstract

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-methoxy-2-oxoethyl)-2-oxopiperazinyl]acetic acid (4), the amidino group was converted to an oxadiazole ring, thiadiazole ring or substituted amidoxime group. 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 platelets. Among the compounds examined, the methoxycarbonyloxyamidine 8a exhibited the most potent ex vivo inhibitory activity with a fast onset and prolonged duration of action after oral administration.

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