Novel O-glucosides of the recently reported potent factor Xa (fXa) inhibitors,(1) which bear 5- chlorothien-2-yl moiety and 1-isopropylpiperidine as the fragments binding the S1 and S4 enzyme pockets, respectively, were synthesized. In particular, β-D-glucose was conjugated through an ether-linked C3-alkyl spacer to the central phenyl ring of the most potent inhibitor, providing a β-D-glucosyl derivative which showed picomolar inhibition potency against human fXa (Ki = 60 pM), nanomolar potency against thrombin (fIIa, Ki = 60 nM) and high selectivity over a panel of other serine proteases, including trypsin and leukocyte elastase, as well as in vitro sub-micromolar anticoagulant activity in the prothrombin time (PT) clotting assay and a statistically significant 1.6-fold prolongation of the basal PT in an ex vivo assay in mice. The crystal structures of human thrombin in complex with two highly potent glucose-based compounds were solved, which provided us with useful information on the binding modes of these inhibitors. While as expected from previous studies(2) the chlorothiophene group binds in the S1 pocket and the N1-isopropylpiperidine group in the S4 region, the sugar moiety binds in a protein region hitherto unexploited by small-molecule direct fIIa inhibitors, which is located near the S4 subsite, where the glucose O2 form strong H-bonds with two basic residues, i.e., Arg221A and Lys224.

NOVEL GLUCOSE-CONJUGATED HIGHLY POTENT DUAL THROMBIN AND FACTOR Xa INHIBITORS AS POTENTIAL ANTITHROMBOTICS

DE CANDIA, MODESTO;Colucci M;ALTOMARE, Cosimo Damiano
2013

Abstract

Novel O-glucosides of the recently reported potent factor Xa (fXa) inhibitors,(1) which bear 5- chlorothien-2-yl moiety and 1-isopropylpiperidine as the fragments binding the S1 and S4 enzyme pockets, respectively, were synthesized. In particular, β-D-glucose was conjugated through an ether-linked C3-alkyl spacer to the central phenyl ring of the most potent inhibitor, providing a β-D-glucosyl derivative which showed picomolar inhibition potency against human fXa (Ki = 60 pM), nanomolar potency against thrombin (fIIa, Ki = 60 nM) and high selectivity over a panel of other serine proteases, including trypsin and leukocyte elastase, as well as in vitro sub-micromolar anticoagulant activity in the prothrombin time (PT) clotting assay and a statistically significant 1.6-fold prolongation of the basal PT in an ex vivo assay in mice. The crystal structures of human thrombin in complex with two highly potent glucose-based compounds were solved, which provided us with useful information on the binding modes of these inhibitors. While as expected from previous studies(2) the chlorothiophene group binds in the S1 pocket and the N1-isopropylpiperidine group in the S4 region, the sugar moiety binds in a protein region hitherto unexploited by small-molecule direct fIIa inhibitors, which is located near the S4 subsite, where the glucose O2 form strong H-bonds with two basic residues, i.e., Arg221A and Lys224.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11586/136495
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