RT Journal Article
SR Electronic
T1 A Pregnane X Receptor Agonist with Unique Species-Dependent Stereoselectivity and Its Implications in Drug Development
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 403
OP 413
DO 10.1124/mol.105.013292
VO 68
IS 2
A1 Ying Mu
A1 Corey R. J. Stephenson
A1 Christopher Kendall
A1 Simrat P. S. Saini
A1 David Toma
A1 Songrong Ren
A1 Hongbo Cai
A1 Stephen C. Strom
A1 Billy W. Day
A1 Peter Wipf
A1 Wen Xie
YR 2005
UL http://molpharm.aspetjournals.org/content/68/2/403.abstract
AB 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.