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Potent In-vitro and In-vivo Inhibitors of Platelet-aggregation Based Upon the Arg-gly-asp Sequence of Fibrinogen - (aminobenzamidino)succinyl (abas) Series of Orally-active Fibrinogen Receptor Antagonists
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Potent In-vitro and In-vivo Inhibitors of Platelet-aggregation Based Upon the Arg-gly-asp Sequence of Fibrinogen - (aminobenzamidino)succinyl (abas) Series of Orally-active Fibrinogen Receptor Antagonists
Our initial orally active fibrinogen receptor antagonist benzamidinopentanoyl (BAP) series which was discovered through truncation of our iv antiplatelet agent (SC-52012) demonstrated modest oral activity in canine studies (ethyl [5-(4-amidinophenyl)pentanoyl]3-3-amino-3 pyridyl)propionate, 1e). Introduction of an amide bond adjacent to the benzamidine led to a novel series with an (aminobenzamidino)succinyl (ABAS) Arg-Gly surrogate that had improved in vitro potency (5-17 times) relative to the BAP series. Four ester prodrug/acid active metabolite pairs (2a/2e, 60a/60e, 62a/62e, 63a/63e) from the ABAS series which varied in their 3-substituent on the beta-amino ester ''aspartate mimetic'' were prepared in enantiomerically enriched form (>95:5), and they were evaluated in canine studies for their ability to block collagen-induced aggregation in platelet-rich plasma, the elimination profile (t(1/2) beta-phase), repeated oral dosing studies, and oral systemic availability. Of the four ester prodrug/acid active metabolite pairs, 2e/2a (SC-54684A/SC-54701A) had the most favorable properties in the above studies with an IC50 = 67 +/- 5 nM (dog platelet-rich plasma, collagen), t(1/2) beta = 1.6 h tester) and 6.5 h (acid), no adverse effects upon repeated dosing, and a drug oral systemic availability of 62% (area under curve (AUG) of acid 2a (drug) following ig administration of ester 2e (prodrug, 2.5 mg/kg) divided by AUC of acid 2a (drug) following iv administration of ester 2e (prodrug, 2.5 mg/kg) as determined by HPLRC). In further pharmacokinetic studies using nonlabeled 2e/2a, the oral systemic availability tester 2e ig/ester 2e iv) of 2e was measured to be in the range of 44.7-53.0%. The more biologically relevant oral systemic availability tester 2e ig/acid 2a iv) of 2e was found to be in the range of 22.0-26.4%. A pharmacophore model. based on inhibitors from several different benzamidine classes including 2a (ABAS class) was developed using a combination of molecular modeling (MM2) and pharmacophore identification (APOLLO) methods.
Zablocki, JA. ; et. al. Potent In-vitro and In-vivo Inhibitors of Platelet-aggregation Based Upon the Arg-gly-asp Sequence of Fibrinogen - (aminobenzamidino)succinyl (abas) Series of Orally-active Fibrinogen Receptor Antagonists. In: Journal of Medicinal Chemistry, Vol. 38, no. 13, p. 2378-2394 (1995)