Synthesis of novel ketoconazole derivatives as inhibitors of the human Pregnane X Receptor (PXR; NR1I2; also termed SXR, PAR)

Bhaskar C. Das, Ankanahlli V. Madhukumar, Jaime Anguiano, Sean Kim, Michael Sinz, Tatyana A. Zvyaga, Eoin C. Power, C. Robin Ganellin, Sridhar Mani

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


PXR, pregnane X receptor, in its activated state, is a validated target for controlling certain drug-drug interactions in humans. In this context, there is a paucity of inhibitors directed toward activated PXR. Using prior observations with ketoconazole as a PXR inhibitor, the target compound 3 was synthesized from (s)-glycidol with overall 56% yield. (+)-Glycidol was reacted with 4-bromophenol and potassium carbonate in DMF to yield the ring opened compound 6. This was then heated to reflux in benzene along with 2′, 4′-difluoroacetophenone and catalytic amount of para-toluene sulfonic acid to yield 8. The resultant acetal 8 was then functionalized using Palladium chemistry to yield the target compound 3. The activity of the compound was compared with ketoconazole and UCL2158H. However, in contrast with ketoconazole (IC50 ∼ 0.020 μM; ∼100% inhibition), 3 has negligible effects on inhibition of microsomal CYP450 (maximum ∼20% inhibition) at concentrations >40 μM. In vitro, micromolar concentration of ketoconazole is toxic to passaged human cell lines, while 3 does not exhibit cytotoxicity up to concentrations ∼100 μM (viability >85%). This is the first demonstration of a chemical analog of a PXR inhibitor that retains activity against activated PXR. Furthermore, in contrast with ketoconazole, 3 is less toxic in human cell lines and has negligible CYP450 activity.

Original languageEnglish (US)
Pages (from-to)3974-3977
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Issue number14
StatePublished - Jul 15 2008


  • Analogs
  • Azole
  • Ketoconazole
  • Nuclear receptors
  • PXR
  • Pregnane X receptor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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