Aromatic 2-(Thio)ureidocarboxylic Acids As a New Family of Modulators of Multidrug Resistance-Associated Protein 1: Synthesis, Biological Evaluation, and Structure-Activity Relationships

作者：Haecker Hans Georg; Leyers Stefan; Wiendlocha Jeanette; Guetschow Michael; Wiese Michael

来源：Journal of Medicinal Chemistry, 2009, 52(15): 4586-4595.

DOI：10.1021/jm900688v

Four series of aromatic carboxylic acids were prepared with a urea or thiourea moiety at the neighboring position to the carboxyl group and benzene or thiophene as aromatic scaffold. Using a calcein AM assay, these compounds were evaluated as inhibitors of multidrug resistance-associated protein I (MRP1) and selected compounds were examined toward P-glycoprotein (P-gp) as well as breast cancer resistance protein (BCRP) to assess selectivity for MRP1. Two 2-thioureidobenzo[b]-thiophene-3-carboxylic acids (48, 49) were identified as particularly potent inhibitors of MRP1, with IC(50) values of around 1 mu M. The structural features of this new family or nontoxic MRP1 inhibitors include a (thio)urea disubstituted with preferentially two alkyl groups at the terminal nitrogen and an additional fused aromatic ring.

• 出版日期2009-8-13