Identification of Novel Nonsteroidal Compounds as Substrates or Inhibitors of hASBT

A prodrug approach that employs the human apical sodium dependent bile acid transporter (hASBT) for absorption requires a recognition moiety for hASBT. Bile acids are natural ligands for hASBT, but are hormones with high molecular weight, such that a recognition moiety that is not a bile acid may be advantageous. The objective was to identify nonsteroidal small molecules that could potentially serve as promoieties in the design of prodrugs that target hASBT. Three searches for bile acid analogues were conducted and it involved molecular fingerprints as the computational tools for similarity searching, as well as traditional medicinal chemistry pattern recognition. Sixty-three compounds were tested using a hASBT-Madin-Darby canine kidney cell monolayer model. Twenty-three of these compounds were found to be hASBT inhibitors and represent novel hASBT inhibitors. Three were selected for hASBT uptake studies. Two were substrates, which represent the first reported nonsteroidal substrates of hASBT. Interestingly, each compound lacked a negative charge. These compounds promise to serve as leads to identify hASBT recognition moieties in a prodrug approach to target hASBT to increase drug absorption. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association.