Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 1. The selection of naphthalene derivatives.
The synthesis and design using molecular modeling techniques for non-peptide, low molecular weight novel fibrinogen receptor (glycoprotein IIb/IIIa: Gp IIb/IIIa) antagonists, is reported. We used a highly potent serine protease inhibitor, Nafamostat, having an amidinonaphthyl unit as the starting compound. The compounds 4-(6-amidino-2-naphthylaminocarbonyl)phenoxyacetic acid (5a) and 4-(6-amidino-2-naphthalenecarboxamido)phenoxyacetic acid (5b) inhibited adenosin-5'-diphospate (ADP)-induced aggregation of human platelet-rich plasma (PRP) with IC50 values of 0.05 and 0.07 microM, respectively, and had lost their ability to inhibit a variety of serine proteases, including thrombin, factor Xa, plasmin and trypsin.
Ono
S
S
Drug Discovery Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Osaka, Japan.
Inoue
Y
Y
Yoshida
T
T
Ashimori
A
A
Kosaka
K
K
Imada
T
T
Fukaya
C
C
Nakamura
N
N
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000478:Alkylation; D001550:Benzamidines; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008970:Molecular Weight; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology
D001550:Benzamidines; D006146:Guanidines; D009281:Naphthalenes; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D015842:Serine Proteinase Inhibitors; D000244:Adenosine Diphosphate; C032855:nafamostat