title: Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 1. The selection of naphthalene derivatives.
abstract: 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.
authors.affiliation: Drug Discovery Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ono
authors.forename: Y
authors.initials: Y
authors.lastname: Inoue
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
authors.forename: A
authors.initials: A
authors.lastname: Ashimori
authors.forename: K
authors.initials: K
authors.lastname: Kosaka
authors.forename: T
authors.initials: T
authors.lastname: Imada
authors.forename: C
authors.initials: C
authors.lastname: Fukaya
authors.forename: N
authors.initials: N
authors.lastname: Nakamura
mesh_terms: 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
chemical_list: 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