Received for publication March 29, 2005.
Revised May 4, 2005.
Accepted for publication May 4, 2005.

A PXR Agonist with Unique Species-Dependent Stereoselectivity and Its Implications in Drug Development

Abstract

Pregnane X receptor (PXR) is an orphan nuclear receptor that regulates the expression of genes encoding drug metabolizing enzymes and transporters. In addition to impacting drug metabolism, potent and selective PXR agonists may also have therapeutic potential by removing endogenous and exogenous toxins. Here 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 hPXR agonist, (+)-S20 was more potent and efficacious than rifampicin. Mutagenesis studies revealed that the LBD residue F305 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 effect when a xenobiotic receptor is being used as a drug target.

Key words: Regulation - transcriptional, Regulation - xenobiotic

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