Design and Synthesis of an orally active GPIIb/IIIa antagonist based on a phenylpiperazine scaffold

The design and synthesis of an orally active LMW non-peptide GPIIb/IIIa antagonist, based on a N, N′-bisphenylpiperazine scaffold, is described. The optimal compound showed a high in vitro binding potency (pIC 50=8.7) in combination with potent oral antithrombotic activity (30–40% inhibition of thro...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 1998-06, Vol.8 (12), p.1531-1536
Hauptverfasser:	van Maarseveen, Jan H, den Hartog, Jack A.J, Tipker, Koos, Reinders, Jan-Hendrik, Brakkee, Joost, Schön, Uwe, Kehrbach, Wolfgang, Kruse, Chris G
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals antagonists anticoagulants Biological and medical sciences Blood. Blood coagulation. Reticuloendothelial system Cricetinae Drug Design Fibrinolytic Agents - chemical synthesis Fibrinolytic Agents - chemistry Fibrinolytic Agents - pharmacology Guinea Pigs Humans isosteres Magnetic Resonance Spectroscopy Mass Spectrometry Medical sciences molecular modelling/mechanics Pharmacology. Drug treatments Piperazines - chemistry Platelet Aggregation Inhibitors - chemical synthesis Platelet Aggregation Inhibitors - chemistry Platelet Aggregation Inhibitors - pharmacology Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors Thrombosis - prevention & control
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Zusammenfassung:	The design and synthesis of an orally active LMW non-peptide GPIIb/IIIa antagonist, based on a N, N′-bisphenylpiperazine scaffold, is described. The optimal compound showed a high in vitro binding potency (pIC 50=8.7) in combination with potent oral antithrombotic activity (30–40% inhibition of thrombus growth at 0.3–3 mg/kg) with a duration of action of >90 min. in a hamster cheek pouch model. Graphic
ISSN:	0960-894X 1464-3405
DOI:	10.1016/S0960-894X(98)00257-1