Zarghi Afshin, Javid Farin Sattary, Ghodsi Razieh, Dadrass Orkideh G, Daraei Bahram, Hedayati Mehdi
Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Sci Pharm. 2011 Jul-Sep;79(3):449-60. doi: 10.3797/scipharm.1104-20. Epub 2011 Jul 25.
A new group of 5,5-diarylhydantoin derivatives bearing a methylsulfonyl COX-2 pharmacophore at the para position of the C-5 phenyl ring were designed and synthesized as selective COX-2 inhibitors. In vitro COX-1/COX-2 inhibition structure-activity relationships identified 5-[4-(methylsulfonyl)phenyl]-5-phenyl-hydantoin (4) as a highly potent and selective COX-2 inhibitor (COX-2 IC(50) = 0.077 μM; selectivity index > 1298). It was more selective than the reference drug celecoxib (COX-2 IC(50) = 0.060 μM; selectivity index = 405). A molecular modeling study where 4 was docked in the binding site of COX-2 indicated that the p-MeSO(2) COX-2 pharmacophore group on the C-5 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket. The results of this study showed that the type of substituent on the N-3 hydantoin ring substituent is important for COX-2 inhibitory activity.
设计并合成了一组新型的5,5-二芳基乙内酰脲衍生物，这些衍生物在C-5苯环的对位带有甲磺酰基COX-2药效基团，作为选择性COX-2抑制剂。体外COX-1/COX-2抑制构效关系确定5-[4-(甲磺酰基)苯基]-5-苯基乙内酰脲(4)为一种高效且选择性的COX-2抑制剂(COX-2 IC(50)=0.077μM；选择性指数>1298)。它比参比药物塞来昔布更具选择性(COX-2 IC(50)=0.060μM；选择性指数=405)。一项将4对接至COX-2结合位点的分子模拟研究表明，C-5苯环上的对甲磺酰基COX-2药效基团位于COX-2二级口袋附近。该研究结果表明，N-3乙内酰脲环取代基上的取代基类型对COX-2抑制活性很重要。
