三环异恶唑是多药耐药蛋白（MRP1）的新型抑制剂。

Tricyclic isoxazoles are novel inhibitors of the multidrug resistance protein (MRP1).

作者信息

Norman Bryan H, Gruber Joseph M, Hollinshead Sean P, Wilson Joseph W, Starling James J, Law Kevin L, Self Tracy D, Tabas Linda B, Williams Daniel C, Paul Donald C, Wagner Margaret M, Dantzig Anne H

机构信息

Discovery Chemistry Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.

出版信息

Bioorg Med Chem Lett. 2002 Mar 25;12(6):883-6. doi: 10.1016/s0960-894x(02)00051-3.

DOI:10.1016/s0960-894x(02)00051-3

PMID:11958985

Abstract

Tricyclic isoxazoles were identified from a screen as a novel class of selective multidrug resistance protein (MRP1) inhibitors. From a screen lead, SAR efforts resulted in the preparation of LY 402913 (9h), which inhibits MRP1 and reverses drug resistance to MRP1 substrates, such as doxorubicin, in HeLa-T5 cells (EC(50)=0.90 microM), while showing no inherent cytotoxicity. Additionally, LY 402913 inhibits ATP-dependent, MRP1-mediated LTC(4) uptake into membrane vesicles prepared from the MRP1-overexpressing HeLa-T5 cells (EC(50)=1.8 microM). LY 402913 also shows selectivity ( approximately 22-fold) against the related transporter, P-glycoprotein, in HL60/Adr and HL60/Vinc cells. Finally, when dosed in combination with the oncolytic MRP1 substrate vincristine, LY 402913 delays the growth of MRP1-overexpressing tumors in vivo.

摘要

通过筛选发现三环异恶唑是一类新型的选择性多药耐药蛋白（MRP1）抑制剂。从筛选得到的先导化合物出发，通过构效关系研究制备出了LY 402913（9h），它能抑制MRP1并逆转HeLa-T5细胞对MRP1底物（如阿霉素）的耐药性（EC(50)=0.90 microM），同时不表现出内在细胞毒性。此外，LY 402913能抑制ATP依赖的、由MRP1介导的白三烯C4（LTC(4)）摄取到从过表达MRP1的HeLa-T5细胞制备的膜囊泡中（EC(50)=1.8 microM）。在HL60/Adr和HL60/Vinc细胞中，LY 402913对相关转运蛋白P-糖蛋白也表现出选择性（约22倍）。最后，当与溶瘤性MRP1底物长春新碱联合给药时，LY 402913能在体内延缓过表达MRP1的肿瘤生长。