title: 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.
abstract: Our initial orally active fibrinogen receptor antagonist benzamidinopentanoyl (BAP) series which was discovered through truncation of our i.v. antiplatelet agent (SC-52012) demonstrated modest oral activity in canine studies (ethyl [5-(4-amindinophenyl)pentanoyl]-3-amino-3-(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 (t1/2 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) has the most favorable properties in the above studies with an IC50 = 67 +/- 5 nM (dog platelet-rich plasma, collagen), t1/2 beta = 1.6 h (ester) and 6.5 h (acid), no adverse effects upon repeated dosing, and a drug oral systemic availability of 62% (area under curve (AUC) of acid 2a (drug) following ig administration of ester 2e (prodrug, 2.5 mg/kg) divided by AUC of acid 2a (drug) following i.v. 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 (ester 2e ig/ester 2e i.v.) of 2e was measured to be in the range of 44.7-53.0%. The more biologically relevant oral systemic availability (ester 2e ig/acid 2a i.v.) 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.
authors.affiliation: Department of Medicinal Chemistry, Searle Research & Development, Skokie, Illinois 60077, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Zablocki
authors.forename: J G
authors.initials: JG
authors.lastname: Rico
authors.forename: R B
authors.initials: RB
authors.lastname: Garland
authors.forename: T E
authors.initials: TE
authors.lastname: Rogers
authors.forename: K
authors.initials: K
authors.lastname: Williams
authors.forename: L A
authors.initials: LA
authors.lastname: Schretzman
authors.forename: S A
authors.initials: SA
authors.lastname: Rao
authors.forename: P R
authors.initials: PR
authors.lastname: Bovy
authors.forename: F S
authors.initials: FS
authors.lastname: Tjoeng
authors.forename: R J
authors.initials: RJ
authors.lastname: Lindmark
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001550:Benzamidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D005340:Fibrinogen / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D013386:Succinates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001550:Benzamidines; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D013386:Succinates; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen