A novel series of orally active antiplatelet agents.
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).
Zablocki
J A
JA
Department of Medicinal Chemistry, Searle Research & Development, Skokie, IL 60077, USA.
Tjoeng
F S
FS
Bovy
P R
PR
Miyano
M
M
Garland
R B
RB
Williams
K
K
Schretzman
L
L
Zupec
M E
ME
Rico
J G
JG
Lindmark
R J
RJ
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
C095308:5-(4-amidinophenyl)pentanoyl-aspartyl-phenylalanine; D004151:Dipeptides; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D003094:Collagen