Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability

The only oral direct thrombin inhibitors
that have reached the
market, ximelagatran and dabigatran etexilat, are double prodrugs
with low bioavailability in humans. We have evaluated an alternative
strategy: the preparation of a nonpeptidic, polar direct thrombin
inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)­alkoxy
prodrug. Two homologous prodrugs were synthesized and displayed high
solubilities and Caco-2 cell permeabilities, suggesting high absorption
from the intestine. In addition, they were rapidly and completely
converted to the active zwitterionic thrombin inhibitor in human hepatocytes.
Unexpectedly, the most promising prodrug displayed only moderately
higher oral bioavailability in rat than the polar direct thrombin
inhibitor, most likely due to rapid metabolism in the intestine or
the intestinal wall. To the best of our knowledge, this is the first
in vivo ADME study of macrocyclic (acyloxy)­alkoxy prodrugs, and it
remains to be established if the modest increase in bioavailability
is a general feature of this category of prodrugs or not.