Novel strategy to boost oral anticoagulant activity of blood coagulation enzyme inhibitors based on biotransformation into hydrophilic conjugates

In this article, we propose a novel strategy towards discovery for orally active anticoagulants. This strategy is based on bioconversion from a nonamidine-type blood coagulation cascade inhibitor into the corresponding conjugate, which boosts ex vivo anticoagulant activity owing to an increase in hy...

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Veröffentlicht in:Bioorganic & medicinal chemistry 2014-11, Vol.22 (22), p.6324-6332
Hauptverfasser: Ishihara, Tsukasa, Koga, Yuji, Mori, Kenichi, Sugasawa, Keizo, Iwatsuki, Yoshiyuki, Hirayama, Fukushi
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Sprache:eng
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Zusammenfassung:In this article, we propose a novel strategy towards discovery for orally active anticoagulants. This strategy is based on bioconversion from a nonamidine-type blood coagulation cascade inhibitor into the corresponding conjugate, which boosts ex vivo anticoagulant activity owing to an increase in hydrophilicity. Computational molecular modeling enabled us to rationally select a template scaffold and design a series of novel inhibitors. Our study resulted in the identification of the phenol-containing fXa inhibitor ASP8102 (14) with excellent oral anticoagulant activity, which was biotransformed into the active glucuronide 16 after oral dosing. [Display omitted] The blood coagulation cascade represents an attractive target for antithrombotic drug development, and recent studies have attempted to identify oral anticoagulants with inhibitory activity for enzymes in this cascade, with particular attention focused on thrombin and factor Xa (fXa) as typical targets. We previously described the discovery of the orally active fXa inhibitor darexaban (1) and reported a unique profile that compound 1 rapidly transformed into glucuronide YM-222714 (2) after oral administration. Here, we propose a novel strategy towards the discovery of an orally active anticoagulant that is based on the bioconversion of a non-amidine inhibitor into the corresponding conjugate to boost ex vivo anticoagulant activity via an increase in hydrophilicity. Computational molecular modeling was utilized to select a template scaffold and design a substitution point to install a potential functional group for conjugation. This strategy led to the identification of the phenol-derived fXa inhibitor ASP8102 (14), which demonstrated highly potent anticoagulant activity after biotransformation into the corresponding glucuronide (16) via oral dosing.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2014.09.059