Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA, USA.
Eur J Med Chem. 2023 Nov 5;259:115666. doi: 10.1016/j.ejmech.2023.115666. Epub 2023 Jul 20.
ATP-binding cassette subfamily G member 2 (ABCG2), an efflux transporter, is involved in multiple pathological processes. Ko143 is a potent ABCG2 inhibitor; however, it is quickly metabolized through carboxylesterase 1-mediated hydrolysis of its t-butyl ester moiety. The current work aimed to develop more metabolically stable ABCG2 inhibitors. Novel Ko143 analogs were designed and synthesized by replacing the unstable t-butyl ester moiety in Ko143 with an amide group. The synthesized Ko143 analogs were evaluated for their ABCG2 inhibitory activity, binding mode with ABCG2, cytotoxicity, and metabolic stability. We found that the amide modification of Ko143 led to metabolically stable ABCG2 inhibitors. Among these Ko143 analogs, K2 and K34 are promising candidates with favorable oral pharmacokinetic profiles in mice. In summary, we synthesized novel Ko143 analogs with improved metabolic stability, which can potentially be used as lead compounds for the future development of ABCG2 inhibitors.
三磷酸腺苷结合盒亚家族 G 成员 2（ABCG2）是一种外排转运蛋白，参与多种病理过程。Ko143 是一种有效的 ABCG2 抑制剂；然而，它通过羧酸酯酶 1 介导的其叔丁酯部分的水解而迅速代谢。本研究旨在开发更稳定代谢的 ABCG2 抑制剂。通过用酰胺基团替代 Ko143 中不稳定的叔丁酯部分来设计和合成新型 Ko143 类似物。评估了合成的 Ko143 类似物的 ABCG2 抑制活性、与 ABCG2 的结合模式、细胞毒性和代谢稳定性。我们发现 Ko143 的酰胺修饰导致代谢稳定的 ABCG2 抑制剂。在这些 Ko143 类似物中，K2 和 K34 是有前途的候选药物，在小鼠中具有良好的口服药代动力学特征。总之，我们合成了具有改善代谢稳定性的新型 Ko143 类似物，它们可能被用作未来开发 ABCG2 抑制剂的先导化合物。
