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Drug Metabolism and Disposition Fast Forward
First published on December 7, 2004; DOI: 10.1124/dmd.104.002089

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Received for publication August 31, 2004.
Revised December 2, 2004.
Accepted for publication December 2, 2004.

New 4-Aryl-1,4-Dihydropyridines and 4-Arylpyridines as P-glycoprotein Inhibitors

Xiao-fei Zhou 1, Linping Zhang 2, Elaine Tseng 3, Elizabeth A Scott-Ramsay 1, Jerome J Schentag 1, Robert A Coburn 1, Marilyn E Morris 1*

1 University at Buffalo 2 Infinity Pharmaceuticals, Inc. 3 Pfizer Global Research and Development

* Address correspondence to: E-mail: memorris{at}buffalo.edu

Abstract

Efflux of cytotoxic agents mediated by P-glycoprotein is believed to be an important mechanism of multidrug resistance (MDR), which remains a serious limitation to successful chemotherapy in cancers such as metastatic breast cancer. A series of 4-aryl-1,4-dihydropyridines and corresponding aromatized 4-arylpyridines have been synthesized based on structure modifications of niguldipine in order to enhance MDR reversal activity, while minimizing calcium channel binding. Thirty new compounds were characterized. [3H]vinblastine accumulation studies indicated that at a concentration level of 3 µM, fifteen out of eighteen 4-aryl-1,4-dihydropyridines and all 4-arylpyridines can successfully restore intracellular accumulation of vinblastine in a resistant human breast adenocarcinoma cell line, MCF-7/adr, which overexpresses P-glycoprotein. The most potent compounds led to an approximately 15-fold increase of vinblastine accumulation. All of the test compounds that significantly increased vinblastine accumulation in MCF/adr cells were able to substantially reduce IC50 values of daunomycin and increase its cytotoxicity in MCF-7/adr resistant cells, confirming the results of the vinblastine accumulation studies. Calcium channel binding assays for these newly synthesized compounds were conducted using rat cerebral cortex membrane. All but eight compounds demonstrated negligible calcium channel binding over the concentration range from 15 to 2,500 nM. The results demonstrate that the newly synthesized series of 1,4-dihydropyridines and pyridines represent P-glycoprotein modulators with negligible calcium channel blocking activity.


Key words: ABC transporters, multi-drug resistance, p-glycoprotein, transporters


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X.-f. Zhou, X. Yang, Q. Wang, R. A. Coburn, and M. E. Morris
EFFECTS OF DIHYDROPYRIDINES AND PYRIDINES ON MULTIDRUG RESISTANCE MEDIATED BY BREAST CANCER RESISTANCE PROTEIN: IN VITRO AND IN VIVO STUDIES
Drug Metab. Dispos., August 1, 2005; 33(8): 1220 - 1228.
[Abstract] [Full Text] [PDF]


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