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 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.
Zablocki
J A
JA
Department of Medicinal Chemistry, Searle Research & Development, Skokie, Illinois 60077, USA.
Rico
J G
JG
Garland
R B
RB
Rogers
T E
TE
Williams
K
K
Schretzman
L A
LA
Rao
S A
SA
Bovy
P R
PR
Tjoeng
F S
FS
Lindmark
R J
RJ
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*
D001550:Benzamidines; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D013386:Succinates; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen