European Journal of Medicinal Chemistry
European Journal of Medicinal Chemistry
5 years ago

Structure activity relationships, multidrug resistance reversal and selectivity of heteroarylphenyl ABCG2 inhibitors

Structure activity relationships, multidrug resistance reversal and selectivity of heteroarylphenyl ABCG2 inhibitors
An overexpression of the transmembrane ATP-binding cassette transporter G2 (ABCG2, BCRP) in cancer tissues is supposed to play a role in the multidrug resistance (MDR) of tumors resulting in an inefficient chemotherapy. Therefore, co-administration of selective and non-toxic ABCG2 inhibitors is a promising strategy for improving the efficacy of chemotherapy by blocking ABCG2-mediated export of the cytostatic drugs. In the present study, we designed a small library of 38 novel compounds containing a heteroaryl-phenyl scaffold possessing several (bioisosteric) moieties, and twelve new precursors. We investigated the library for ABCG2 inhibition, for the selectivity against MDR-involved efflux pump ABCB1 (P-gp) and for toxicity. Structure activity relationship (SAR) studies revealed that, at least a phenylheteroaryl-phenylamide scaffold is necessary for observing an ABCG2 inhibition. 4-Methoxy-N-(2-(2-(6-methoxypyridin-3-yl)-2H-tetrazol-5-yl)phenyl)benzamide (43) exhibited a high potency (IC50 = 61 nM)), selectivity, low intrinsic toxicity and reversed the ABCG2-mediated drug resistance in presence of only 0.1 μM.

Publisher URL: www.sciencedirect.com/science

DOI: S0223523418300126

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