title: A novel series of orally active antiplatelet agents.
abstract: A novel series of orally active fibrinogen receptor antagonists has been discovered through structural modification of our lead intravenous (iv) antiplatelet agent, 5-(4-amidinophenyl)pentanoyl-Asp-Phe 1 (SC-52012). The Asp-Phe amide bond was removed through truncation to a 3-substituted beta-amino acid aspartate mimetic which resulted in a tripeptide mimetic inhibitor of lower molecular weight (from 482 to the 330-390 g mol-1). The zwitterionic nature of the inhibitor was masked through the preparation of an ethyl ester prodrug. A lead compound from this series, 5-(4-amidinophenyl)pentanoyl-3-(3-pyridyl)propanoic acid 19a, was found to be a potent inhibitor of canine platelet aggregation in vitro (collagen, platelet rich plasma, PRP, IC50 = 270 nM). In further canine studies, oral administration of different ester pro-drugs of 19a at 10 mg kg-1 resulted in the following oral systemic activities: pivaloyloxymethyl ester derivative 19p (5.1 +/- 1.5% OSA), cyclohexyl ester derivative 19c (9.2 +/- 1.9% OSA), and ethyl ester derivative 19e (9.9 +/- 2.3% OSA).
authors.affiliation: Department of Medicinal Chemistry, Searle Research & Development, Skokie, IL 60077, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Zablocki
authors.forename: F S
authors.initials: FS
authors.lastname: Tjoeng
authors.forename: P R
authors.initials: PR
authors.lastname: Bovy
authors.forename: M
authors.initials: M
authors.lastname: Miyano
authors.forename: R B
authors.initials: RB
authors.lastname: Garland
authors.forename: K
authors.initials: K
authors.lastname: Williams
authors.forename: L
authors.initials: L
authors.lastname: Schretzman
authors.forename: M E
authors.initials: ME
authors.lastname: Zupec
authors.forename: J G
authors.initials: JG
authors.lastname: Rico
authors.forename: R J
authors.initials: RJ
authors.lastname: Lindmark
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003094:Collagen / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D066298:In Vitro Techniques; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C095308:5-(4-amidinophenyl)pentanoyl-aspartyl-phenylalanine; D004151:Dipeptides; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D003094:Collagen