Document Detail


Identification of novel nonsteroidal compounds as substrates or inhibitors of hASBT.
MedLine Citation:
PMID:  22109685     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
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 J Pharm Sci 101:116-126, 2012.
Authors:
Vidula Kolhatkar; Lei Diao; Chayan Acharya; Alexander D Mackerell; James E Polli
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Publication Detail:
Type:  Journal Article     Date:  2011-08-25
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  101     ISSN:  1520-6017     ISO Abbreviation:  J Pharm Sci     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2011-11-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985195R     Medline TA:  J Pharm Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  116-26     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Wiley-Liss, Inc.
Affiliation:
University of Maryland School of Pharmacy, Baltimore, Maryland 21201.
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