BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
J Med Chem. 2011 May 26;54(10):3650-60. doi: 10.1021/jm200063s. Epub 2011 May 4.
Dual target inhibitors against COX-2 and LTA(4)H were designed by adding functional groups from a marketed COX-2 inhibitor, Nimesulide, to an existing LTA(4)H inhibitor 1-(2-(4-phenoxyphenoxy) ethyl) pyrrolidine. A series of phenoxyphenyl pyrrolidine compounds were synthesized and tested for their inhibition activities using enzyme assays and human whole blood assay. Introduction of small electron withdrawing groups like NO(2) and CF(3) in the ortho-position of the terminal phenyl ring was found to change the original single target LTA(4)H inhibitor to dual target LTA(4)H and COX-2 inhibitors. Compound 5a and 5m showed dual LTA(4)H and COX-2 inhibition activities in the enzyme assays and the HWB assay with IC(50) values in the micromolar to submicromolar range. As their activities in HWB assay were comparable to the two starting single target inhibitors, the two compounds are promising for further studies. The strategy used in the current study may be generally applicable to other dual target drug designs.
通过在市售 COX-2 抑制剂尼美舒利的基础上添加功能基团，设计了针对 COX-2 和 LTA(4)H 的双重靶标抑制剂，对现有 LTA(4)H 抑制剂 1-(2-(4-苯氧基苯氧基)乙基)吡咯烷进行修饰。合成了一系列苯氧基苯基吡咯烷化合物，并通过酶测定和人全血测定对其抑制活性进行了测试。在末端苯环的邻位引入小的吸电子基团，如 NO(2)和 CF(3)，将原来的单一靶标 LTA(4)H 抑制剂转变为双重靶标 LTA(4)H 和 COX-2 抑制剂。化合物 5a 和 5m 在酶测定和 HWB 测定中均表现出双重 LTA(4)H 和 COX-2 抑制活性，IC(50)值在微摩尔至亚微摩尔范围内。由于它们在 HWB 测定中的活性与两种起始的单靶标抑制剂相当，因此这两种化合物具有进一步研究的潜力。本研究中使用的策略可能普遍适用于其他双重靶标药物设计。
