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

Journal of Medicinal Chemistry
Janez IlašDanijel Kikelj

Abstract

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.

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Citations

Jul 2, 2015·Future Medicinal Chemistry·Zhouling XieZhiyu Li
May 7, 2013·European Journal of Medicinal Chemistry·Uroš TrstenjakDanijel Kikelj
Oct 30, 2016·The Journal of Organic Chemistry·Eun-Kyung JungDavid Barker
Mar 9, 2017·Journal of Medicinal Chemistry·Claudia FerroniGreta Varchi
Feb 18, 2015·Organic & Biomolecular Chemistry·Khac Minh Huy NguyenMartine Largeron
Jan 6, 2010·Journal of Cellular Physiology·ZhiWu DongJunYing Miao
Aug 26, 2015·ChemMedChem·Daniela HäußlerMichael Gütschow
Jun 13, 2020·Chemical Communications : Chem Comm·Kui DongQiang Liu
Nov 16, 2016·Future Medicinal Chemistry·Ana R NevesMadalena Pinto
Jan 22, 2011·The Journal of Organic Chemistry·Michelle Cortes-SalvaJon C Antilla

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