Design and synthesis of a novel synthetic NAPAP-penta-saccharide conjugate displaying a dual antithrombotic action.
The synthesis of a novel antithrombotic consisting of a heparin pentasaccharide conjugated to the active site inhibitor N-(2-naphtalenesulfonyl)-glycyl-(D)-4-aminophenyl-alanyl-piperidin e (NAPAP) (i.e. compound I) is reported. This conjugate shows a unique pharmacological profile both in vitro and in vivo having direct anti-thrombin and ATIII-mediated anti-Xa activity. Furthermore, conjugate I has a prolonged in vivo half-life compared to NAPAP (1.5 h vs 9 min.).
Buijsman
R C
RC
Leiden Institute of Chemistry, Gorlaeus Laboratories, The Netherlands.
Basten
J E
JE
van Dinther
T G
TG
van der Marel
G A
GA
van Boeckel
C A
CA
van Boom
J H
JH
D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis* / Q000494:pharmacology*; D002240:Carbohydrate Sequence; D004151:Dipeptides / Q000737:chemistry*; D015195:Drug Design; D065427:Factor Xa Inhibitors; D006207:Half-Life; D006493:Heparin / Q000737:chemistry; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000138:chemical synthesis*; D010880:Piperidines / Q000737:chemistry*; D051381:Rats; D012995:Solubility; D013917:Thrombin / Q000037:antagonists & inhibitors
D000991:Antithrombins; D004151:Dipeptides; D065427:Factor Xa Inhibitors; D009844:Oligosaccharides; D010880:Piperidines; C038708:N(alpha)-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide; D006493:Heparin; D013917:Thrombin