Campbell Jeffrey A, Bordunov Viola, Broka Chris A, Browner Michelle F, Kress James M, Mirzadegan Tara, Ramesha Chakk, Sanpablo Bong F, Stabler Russell, Takahara Patricia, Villasenor Armando, Walker Keith A M, Wang Jin-Hai, Welch Mary, Weller Paul
Roche Palo Alto, 3431 Hillview Ave, Palo Alto, CA 94304, USA.
Bioorg Med Chem Lett. 2004 Sep 20;14(18):4741-5. doi: 10.1016/j.bmcl.2004.06.075.
The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation of a conformationally more rigid 3-aroyloxy substituent onto the 6-methylsulfonylindole scaffold led to selective, but considerably less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the indole 2-substituent of 3-arylthio-6-methylsulfonylindole inhibitors led to modulation of the COX-2 human whole blood (HWB) potency and selectivity.
通过合理药物设计将3-芳基甲基、3-芳氧基和3-芳硫基部分引入6-甲基磺酰基吲哚骨架，得到了在大鼠角叉菜胶气袋模型中有效的强效、选择性COX-2抑制剂。在6-甲基磺酰基吲哚支架上引入构象更刚性的3-芳酰氧基取代基，得到了选择性但效力显著较低的COX-2抑制剂。3-芳硫基-6-甲基磺酰基吲哚抑制剂的吲哚2-取代基的亲水性和大小的变化导致了COX-2人全血（HWB）效力和选择性的调节。
