title: Synthesis of novel ketoconazole derivatives as inhibitors of the human Pregnane X Receptor (PXR; NR1I2; also termed SXR, PAR).
abstract: 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) approximately 0.020 microM; approximately 100% inhibition), 3 has negligible effects on inhibition of microsomal CYP450 (maximum approximately 20% inhibition) at concentrations >40 microM. In vitro, micromolar concentration of ketoconazole is toxic to passaged human cell lines, while 3 does not exhibit cytotoxicity up to concentrations approximately 100 microM (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.
authors.affiliation: Albert Einstein Cancer Center, Albert Einstein College of Medicine, Department of Developmental and Molecular Biology, Bronx, NY 10463, USA. bdas@aecom.yu.edu
authors.forename: Bhaskar C
authors.initials: BC
authors.lastname: Das
authors.forename: Ankanahlli V
authors.initials: AV
authors.lastname: Madhukumar
authors.forename: Jaime
authors.initials: J
authors.lastname: Anguiano
authors.forename: Sean
authors.initials: S
authors.lastname: Kim
authors.forename: Michael
authors.initials: M
authors.lastname: Sinz
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Zvyaga
authors.forename: Eoin C
authors.initials: EC
authors.lastname: Power
authors.forename: C Robin
authors.initials: CR
authors.lastname: Ganellin
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
mesh_terms: D001665:Binding Sites; D002384:Catalysis; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D015195:Drug Design; D004347:Drug Interactions; D006801:Humans; D020128:Inhibitory Concentration 50; D007654:Ketoconazole / Q000031:analogs & derivatives* / Q000737:chemistry; D008862:Microsomes, Liver / Q000187:drug effects; D008956:Models, Chemical; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole