Antithrombotic therapies could benefit from three new oral active anticoagulants (NOACs), namely dabigatran etexilate, as inhibitor of both free and fibrin-bound thrombin (fIIa), and apixaban (Eliquis) and rivaroxaban (Xarelto), as factor Xa (fXa)-selective inhibitors.1 NOACs show advantages in overcoming some limitations and side effects associated to administration of warfarin and other vitamin K antagonists. Indeed, NOACs exhibit more stable and predictable pharmacokinetics and no or fewer interactions with food and drugs; moreover, they could be administered in standard doses without the need of laboratory monitoring for dose adjustment. Recently, we reported the activity of several N-(2- or 3-methoxyphenyl)piperidine-4-carboxamide derivatives, which proved to selectively inhibit fXa or fIIa, depending upon the moieties they bear as binders of the specificity enzymes’ subsites S1-S4.2-3 Among them, compound 1, bearing 5-chlorothiophen-2-yl and 1-isopropylpiperidin-4-yl moieties as S1 and S4 binders, respectively, proved to be very potent and selective fXa inhibitor, with good in vitro and ex vivo anticoagulant activity. With the aim of improving the physicochemical properties of 1, we synthesized the β-d-glucose-containing derivative 2, which proved to be even more potent competitive inhibitor of fXa (Ki = 0.090 nM) and fIIa (Ki = 100 nM).4 The crystal structure of human fIIa in complex with 2 helped us in explaining the higher potency gain in fIIa inhibition (110-fold) over the parent non-glucosilated compound 1, in comparison with the slight potency increase against fXa (7-fold).5 X-ray crystallography showed that 2 attained a binding mode which involves a H-bond network between the glucose O1’, O3’ and O6’ and the side-chains of R221a and K224 residues belonging to the Na+-binding site, which may allosterically perturb the specificity sites. In order to extend the exploration of the SARs, in this study we modified the sugar moiety and the S4-binding group. The enzymes’ inhibition potencies and antithrombotic activities (i.e., inhibition of thrombin generation and ability to induce fibrinolysis) of the newly synthesized compounds, as well as their physicochemical properties (e.g. solubility, stability) will be presented and discussed.

Anticoagulant activity of new glycoconjugated inhibitors Of factor Xa and thrombin

DE CANDIA, MODESTO;ZAETTA, GIORGIA;DENORA, NUNZIO;CELLAMARE, Saverio;ALTOMARE, Cosimo Damiano
2015-01-01

Abstract

Antithrombotic therapies could benefit from three new oral active anticoagulants (NOACs), namely dabigatran etexilate, as inhibitor of both free and fibrin-bound thrombin (fIIa), and apixaban (Eliquis) and rivaroxaban (Xarelto), as factor Xa (fXa)-selective inhibitors.1 NOACs show advantages in overcoming some limitations and side effects associated to administration of warfarin and other vitamin K antagonists. Indeed, NOACs exhibit more stable and predictable pharmacokinetics and no or fewer interactions with food and drugs; moreover, they could be administered in standard doses without the need of laboratory monitoring for dose adjustment. Recently, we reported the activity of several N-(2- or 3-methoxyphenyl)piperidine-4-carboxamide derivatives, which proved to selectively inhibit fXa or fIIa, depending upon the moieties they bear as binders of the specificity enzymes’ subsites S1-S4.2-3 Among them, compound 1, bearing 5-chlorothiophen-2-yl and 1-isopropylpiperidin-4-yl moieties as S1 and S4 binders, respectively, proved to be very potent and selective fXa inhibitor, with good in vitro and ex vivo anticoagulant activity. With the aim of improving the physicochemical properties of 1, we synthesized the β-d-glucose-containing derivative 2, which proved to be even more potent competitive inhibitor of fXa (Ki = 0.090 nM) and fIIa (Ki = 100 nM).4 The crystal structure of human fIIa in complex with 2 helped us in explaining the higher potency gain in fIIa inhibition (110-fold) over the parent non-glucosilated compound 1, in comparison with the slight potency increase against fXa (7-fold).5 X-ray crystallography showed that 2 attained a binding mode which involves a H-bond network between the glucose O1’, O3’ and O6’ and the side-chains of R221a and K224 residues belonging to the Na+-binding site, which may allosterically perturb the specificity sites. In order to extend the exploration of the SARs, in this study we modified the sugar moiety and the S4-binding group. The enzymes’ inhibition potencies and antithrombotic activities (i.e., inhibition of thrombin generation and ability to induce fibrinolysis) of the newly synthesized compounds, as well as their physicochemical properties (e.g. solubility, stability) will be presented and discussed.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/192277
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