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Synthesis and Biological Evaluation of (Hetero)Arylmethyloxy- and Arylmethylamine-phenyl Derivatives as Potent P-glycoprotein Modulating Agents

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Dipartimento Farmacochimico, Universitá degli Studi di Bari, Via Orabona, 4, 70125 Bari, Italy, and Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno, 6, 56126 Pisa, Italy
* To whom correspondence should be addressed. (N.A.C.) Phone: +39-0805442727 . Fax: +39-0805442231. E-mail: [email protected]. (S.R.) Phone: +39-0502219582 . Fax: +39-0502219605. E-mail: [email protected]
†Universitá degli Studi di Bari.
‡Università di Pisa.
Cite this: J. Med. Chem. 2008, 51, 5, 1415–1422
Publication Date (Web):February 8, 2008
Copyright © 2008 American Chemical Society

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    Abstract Image

    Starting from lead compounds 12b and 28b, previously characterized as P-glycoprotein (P-gp) modulating agents, two series of new compounds were investigated. Compounds 14a,b and 15a,b displayed high P-gp modulating activity in the submicromolar range (EC50 values from 0.25 to 0.80 µM). Moreover, amino derivatives 2327 showed EC50 values ranging from 0.085 to 0.90 µM. In the pyridyl series, the best result has been obtained for 4-pyridyl derivative 17b (EC50 = 0.85 µM). The best P-gp modulating agents 14a,b, 15a,b, and 2327 also have been studied for determining their breast cancer resistance protein (BCRP) inhibition activity. The results demonstrated that only the amino derivatives 2327 displayed moderate BCRP inhibition activity.

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    Elemental analysis of compounds 11a,b, 13a,b, 14a,b, 15a,b, 16a,b, 17a,b, and 2227 and experimental section for key intermediates 18, 20, and 21. This material is available free of charge via the Internet at

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