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Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient

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Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Drug Delivery

Background:

  • Current oral direct thrombin inhibitors (e.g., ximelagatran, dabigatran etexilate) are double prodrugs with limited oral bioavailability.
  • There is a need for alternative prodrug strategies to enhance the delivery of polar direct thrombin inhibitors.

Purpose of the Study:

  • To evaluate a novel prodrug strategy using a single, macrocyclic esterase-cleavable (acyloxy)alkoxy moiety for a nonpeptidic, polar direct thrombin inhibitor.
  • To assess the in vitro and in vivo characteristics of these novel macrocyclic prodrugs.

Main Methods:

  • Synthesis of two homologous macrocyclic (acyloxy)alkoxy prodrugs.
  • Evaluation of solubility and Caco-2 cell permeability for in vitro absorption assessment.
  • Assessment of conversion to the active inhibitor in human hepatocytes.
  • In vivo pharmacokinetic studies in rats to determine oral bioavailability and metabolism.

Main Results:

  • The synthesized prodrugs exhibited high solubility and Caco-2 cell permeability, indicating good potential for intestinal absorption.
  • Rapid and complete conversion to the active thrombin inhibitor was observed in human hepatocytes.
  • The most promising prodrug showed only a moderate increase in oral bioavailability in rats compared to the parent compound, likely due to intestinal metabolism.

Conclusions:

  • Macrocyclic (acyloxy)alkoxy prodrugs represent a viable strategy for delivering polar direct thrombin inhibitors, demonstrating good in vitro absorption and activation.
  • The in vivo efficacy was limited by rapid metabolism, highlighting the need for further optimization of this prodrug class.
  • This study presents the first in vivo ADME evaluation of macrocyclic (acyloxy)alkoxy prodrugs, with further research needed to determine if the observed bioavailability enhancement is general.