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A pregnane X receptor agonist with unique species-dependent stereoselectivity and its implications in drug development

Mu, Y and Stephenson, CRJ and Kendall, C and Saini, SPS and Toma, D and Ren, S and Cai, H and Strom, SC and Day, BW and Wipf, P and Xie, W (2005) A pregnane X receptor agonist with unique species-dependent stereoselectivity and its implications in drug development. Molecular Pharmacology, 68 (2). 403 - 413. ISSN 0026-895X

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Pregnane X receptor (PXR) is an orphan nuclear receptor that regulates the expression of genes encoding drug-metabolizing enzymes and transporters. In addition to affecting drug metabolism, potent and selective PXR agonists may also have therapeutic potential by removing endogenous and exogenous toxins. In this article, we report the synthesis and identification of novel PXR agonists from a library of peptide isosteres. Compound S20, a C-cyclopropylalkylamide, was found to be a PXR agonist with both enantiomer- and species-specific selectivity. S20 has three chiral carbons and was resolved into its two enantiomers. The individual S20 enantiomers exhibited striking mouse/human-specific PXR activation, whereby enantiomer (+)-S20 preferentially activated hPXR, and enantiomer (-)-S20 was a better activator for mPXR. As a human PXR (hPXR) agonist, (+)-S20 was more potent and efficacious than rifampicin. Mutagenesis studies revealed that the ligand binding domain residue Phe305 is critical for the preference for the (-)-S20 enantiomer by the rodent PXR. Treatment of S20 induced the expression of drug-metabolizing enzymes and transporters in reporter gene assays, in primary human hepatocytes, and in "humanized" hPXR transgenic mice. To our knowledge, S20 represents the first compound whose enantiomers have opposite species preference in activating a xenobiotic receptor. The stereoselectivity may be used to guide the development of safer drugs to avoid drug-drug interactions or to achieve human-specific therapeutic effects when a xenobiotic receptor is being used as a drug target. Copyright © 2005 The American Society for Pharmacology and Experimental Therapeutics.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Mu, Y
Stephenson, CRJ
Kendall, C
Saini, SPS
Toma, D
Ren, S
Cai, H
Strom, SC
Day, BW
Wipf, Ppwipf@pitt.eduPWIPF
Xie, W
Date: 1 August 2005
Date Type: Publication
Journal or Publication Title: Molecular Pharmacology
Volume: 68
Number: 2
Page Range: 403 - 413
DOI or Unique Handle: 10.1124/mol.105.013292
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0026-895X
MeSH Headings: Amides--metabolism; Amides--pharmacology; Animals; Combinatorial Chemistry Techniques; Dose-Response Relationship, Drug; Drug Design; Humans; Mice; Mice, Knockout; Mice, Transgenic; Peptide Fragments--chemistry; Peptide Fragments--genetics; Peptide Library; Receptors, Cytoplasmic and Nuclear--agonists; Receptors, Cytoplasmic and Nuclear--metabolism; Receptors, Steroid--agonists; Receptors, Steroid--metabolism; Species Specificity; Stereoisomerism
PubMed ID: 15872116
Date Deposited: 12 Nov 2013 17:16
Last Modified: 13 Oct 2017 23:01


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