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

被引:24
作者
Mu, Y
Stephenson, CRJ
Kendall, C
Saini, SPS
Toma, D
Ren, SR
Cai, HB
Strom, SC
Day, BW
Wipf, P
Xie, W
机构
[1] Univ Pittsburgh, Ctr Pharmacogenet, Pittsburgh, PA 15261 USA
[2] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA
[3] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15261 USA
[4] Univ Pittsburgh, Ctr Chem Methodol & Lib Dev, Pittsburgh, PA 15261 USA
[5] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USA
[6] Univ Pittsburgh, Dept Pharmacol, Pittsburgh, PA 15261 USA
关键词
D O I
10.1124/mol.105.013292
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
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收藏
页码:403 / 413
页数:11
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