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

被引:30
作者
Das, Bhaskar C. [1 ,2 ]
Madhukumar, Ankanahlli V. [3 ]
Anguiano, Jaime [1 ,2 ]
Kim, Sean [4 ]
Sinz, Michael [4 ]
Zvyaga, Tatyana A. [4 ]
Power, Eoin C. [5 ]
Ganellin, C. Robin [6 ]
Mani, Sridhar [3 ]
机构
[1] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Dev & Mol Biol, Bronx, NY 10463 USA
[2] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Nucl Med, Bronx, NY 10463 USA
[3] Bronx Municipal Hosp Ctr, Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USA
[4] Bristol Myers Squibb Co, Wallingford, CT 06492 USA
[5] Sienabiotech SPA, I-53100 Siena, Italy
[6] UCL, Dept Pharmacol, London WC1E 6BT, England
关键词
pregnane X receptor; PXR; ketoconazole; azole; analogs; nuclear receptors;
D O I
10.1016/j.bmcl.2008.06.018
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 similar to 0.020 mu M; similar to 100% inhibition), 3 has negligible effects on inhibition of microsomal CYP450 (maximum similar to 20% inhibition) at concentrations > 40 mu M. In vitro, micromolar concentration of ketoconazole is toxic to passaged human cell lines, while 3 does not exhibit cytotoxicity up to concentrations similar to 100 mu M(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. (c) 2008 Elsevier Ltd. All rights reserved.
引用
收藏
页码:3974 / 3977
页数:4
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