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Structure activity relationships, multidrug resistance reversal and selectivity of heteroarylphenyl ABCG2 inhibitors
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2018-01-11 , DOI: 10.1016/j.ejmech.2018.01.012
Sebastian C. Köhler , Sahel Vahdati , Matthias S. Scholz , Michael Wiese

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.



中文翻译:

杂芳基苯基ABCG2抑制剂的结构活性关系,多药耐药性逆转和选择性

跨膜ATP结合盒转运蛋白G2(ABCG2,BCRP)在癌症组织中的过表达被认为在肿瘤的多药耐药性(MDR)中起着作用,导致化疗效率低下。因此,选择性和无毒的ABCG2抑制剂的共同给药是通过阻止ABCG2介导的细胞生长抑制药物输出来提高化疗疗效的一种有前途的策略。在本研究中,我们设计了一个包含38个新化合物的小型文库,这些新化合物包含具有几个(生物立体异构)部分的杂芳基-苯基骨架和十二个新的前体。我们调查了ABCG2抑制,针对MDR参与的外排泵ABCB1(P-gp)的选择性和毒性的库。结构活动关系(SAR)研究表明,为了观察ABCG2抑制,至少需要苯基杂芳基-苯基酰胺支架。4-甲氧基N-(2-(2-(6-甲氧基-吡啶-3-基)-2 H-四唑-5-基)苯基)苯甲酰胺(43)显示出高效力(IC 50  = 61 nM))给出,选择性,低的内在在只有0.1μM的情况下可降低毒性并逆转ABCG2介导的耐药性

更新日期:2018-01-11
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