3,4-Dihydro-2H-1,4-benzoxazine derivatives combining thrombin inhibitory and glycoprotein IIb/IIIa receptor antagonistic activity as a novel class of antithrombotic compounds with dual function.
3,4-Dihydro-2 H-1,4-benzoxazine derivatives possessing both thrombin inhibitory and glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonistic activities were obtained by combining mimetics of the d-Phe-Pro-Arg pharmacophore of thrombin inhibitors and the Arg-Gly-Asp pharmacophore of GPIIb/IIIa receptor antagonists in the same low molecular weight peptidomimetic compound. Systematic variation of the position of substituents around the 3,4-dihydro- 2H-1,4-benzoxazine nucleus, the distance between the carboxylate and amidine moieties, together with additional substituents to fill the thrombin S 2 and S 3 pockets resulted in compounds displaying submicromolar inhibition constants ( K i) for thrombin and submicromolar IC 50 for inhibition of binding of fibrinogen to platelet GPIIb/IIIa receptor. Some of these compounds, such as 17a, 17b, 17d, and 17h possessing a well balanced activity at both targets, are a good starting point for further optimization. Incorporation of anticoagulant and platelet antiaggregatory activity in the same molecule constitutes a promising approach toward novel antithrombotic agents.
Ilas
Janez
J
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, SI-1000 Ljubljana, Slovenia.
Jakopin
Ziga
Z
Borstnar
Tina
T
Stegnar
Mojca
M
Kikelj
Danijel
D
D000991:Antithrombins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D048588:Benzoxazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D018716:Molecular Mimicry; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization; D013917:Thrombin / Q000378:metabolism
D000991:Antithrombins; D048588:Benzoxazines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013917:Thrombin