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

• Published in: Bioorganic & medicinal chemistry 2008-07, Vol.18 (14), p.3974-3977
• Main Authors: Das, Bhaskar C., Madhukumar, Ankanahlli V., Anguiano, Jaime, Kim, Sean, Sinz, Michael, Zvyaga, Tatyana A., Power, Eoin C., Ganellin, C. Robin, Mani, Sridhar
• Format: Article
• Language: English
• Subjects: Analogs; Azole; Binding Sites; Biological and medical sciences; Catalysis; Cell Line, Tumor; Chemistry, Pharmaceutical - methods; Cytochrome P-450 CYP3A - chemistry; Cytochrome P-450 Enzyme System - chemistry; Drug Design; Drug Interactions; Humans; Inhibitory Concentration 50; Ketoconazole; Ketoconazole - analogs & derivatives; Ketoconazole - chemistry; Medical sciences; Microsomes, Liver - drug effects; Miscellaneous; Models, Chemical; Nuclear receptors; Pharmacology. Drug treatments; Pregnane X Receptor; PXR; Receptors, Steroid - antagonists & inhibitors; Receptors, Steroid - chemistry
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.06.018

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 (IC 50 ∼ 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.