Preparation and Pharmacological Evaluation of Novel Glycoprotein (Gp) IIb/IIIa Antagonists. 1. The Selection of Naphthalene Derivatives

• Published in: Chemical & pharmaceutical bulletin Vol. 47; no. 12; pp. 1685 - 1693
• Main Authors: ONO, Shin'ichiro, INOUE, Yoshihisa, YOSHIDA, Tomohiro, ASHIMORI, Atsuyuki, KOSAKA, Keigo, IMADA, Teruaki, FUKAYA, Chikara, NAKAMURA, Norifumi
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 1999; Pharmaceutical Soc Japan; Maruzen
• Subjects: Adenosine Diphosphate - pharmacology; Alkylation; amidinonaphthyl compound; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Chemical Phenomena; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Chemistry, Physical; Chromatography, High Pressure Liquid; Drug Design; glycoprotein IIb/IIIa; Guanidines - chemistry; Guanidines - pharmacology; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Medical sciences; Molecular Weight; Naphthalenes - chemical synthesis; Naphthalenes - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - pharmacology; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Science & Technology; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; structure-activity relationship; DIPEPTIDE ISOSTERES; amidinonaphthyl compound; DESIGN; IIB-IIIA RECEPTOR; IN-VIVO INHIBITORS; glycoprotein IIb/IIIa; AMIDINOINDOLES; RGD PEPTIDE; POTENT; FIBRINOGEN RECEPTOR ANTAGONISTS; GPIIB/IIIA; structure-activity relationship; BINDING; Coagulation Factor Xa; Thrombin; Anticoagulant; Modeling; Plasmin; Nafamostat; Structure activity relation; Carboxylic acid; Fibrinogen; Molecular model; Bicyclic compound; Antagonist; Chemical synthesis; Biological receptor; Human; Glycoprotein IIbIIIa; Serine endopeptidases; Enzyme; Enzyme inhibitor; Condensed benzenic compound; In vitro; Naphthalene derivatives; Antiplatelet agent; Peptidases; Amidine; Platelet; Trypsin; Hydrolases; Affinity; Benzamide derivatives; Carboxamide; Benzenic compound
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.47.1685

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 μM, respectively, and had lost their ability to inhibit a variety of serine proteases, including thrombin, factor Xa, plasmin and trypsin.