Chen Qiao-Hong, Rao P N Praveen, Knaus Edward E
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Bioorg Med Chem. 2005 Dec 1;13(23):6425-34. doi: 10.1016/j.bmc.2005.06.064. Epub 2005 Aug 15.
A group of regioisomeric 1-(methylsulfonylphenyl)-2-phenylacetylenes possessing a COX-2 SO(2)Me pharmacophore at the para-, meta- or ortho-position of the C-1 phenyl ring, in conjunction with a C-2 phenyl or substituted-phenyl ring substituent (3-F, 3-OMe, 3-OH, 3-OAc, 4-Me), were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. These target linear 1,2-diarylacetylenes were synthesized via a palladium-catalyzed Sonogashira cross-coupling reaction followed by oxidation of the respective 1-(methylthiophenyl)-2-phenylacetylene intermediate. In vitro COX-1/COX-2 isozyme inhibition structure-activity studies identified 1-(3-methylsulfonylphenyl)-2-(4-methylphenyl)acetylene (12d) as a potent COX-2 inhibitor (IC(50) = 0.32 microM) with a high COX-2 selectivity index (SI > 320) comparable to the reference compound rofecoxib (COX-2 IC(50) = 0.50 microM; COX-2 SI > 200). A molecular modeling study where (12d) was docked in the binding site of COX-2 showed that the MeSO(2) COX-2 pharmacophore was positioned in the vicinity of the secondary COX-2 binding site near Val(523). The 1-(4-methylsulfonylphenyl)-2-(3-acetoxyphenyl)acetylene (11f, COX-1 IC(50) = 1.00 microM; COX-2 IC(50) = 0.06 microM; COX-2 SI = 16.7) and 1-(3-methylsulfonylphenyl)-2-(3-acetoxyphenyl)acetylene (12f, COX-1 IC(50) = 6.5 microM; COX-2 IC(50) = 0.05 microM; COX-2 SI = 130) regioisomers exhibited comparable COX-2 inhibition, and moderately lower selective COX-2 selectivity, relative to the reference drug celecoxib (COX-1 IC(50) = 33.1 microM; COX-2 IC(50) = 0.07 microM; COX-2 SI = 472). The most potent anti-inflammatory agent 1-(3-methylsulfonylphenyl)-2-(4-methylphenyl)acetylene (12d) exhibited moderate oral anti-inflammatory activity (ED(50)= 129 mg/kg) at 3 h postdrug administration relative to the reference drug celecoxib (ED(50) = 10.8 mg/kg) in a carrageenan-induced rat paw edema assay. The structure-activity data acquired indicate that the acetylene moiety constitutes a suitable scaffold (template) to design novel acyclic 1,2-diarylacetylenes with selective COX-2, or dual COX-1/COX-2, inhibitory activities.
设计了一组区域异构体1-(甲基磺酰基苯基)-2-苯基乙炔，在C-1苯环的对位、间位或邻位具有COX-2 SO(2)Me药效基团，并与C-2苯环或取代苯环取代基（3-F、3-OMe、3-OH、3-OAc、4-Me）结合，用于评估其作为选择性环氧化酶-2（COX-2）抑制剂的活性。这些目标线性1,2-二芳基乙炔通过钯催化的Sonogashira交叉偶联反应合成，随后氧化相应的1-(甲基硫代苯基)-2-苯基乙炔中间体。体外COX-1/COX-2同工酶抑制结构-活性研究确定1-(3-甲基磺酰基苯基)-2-(4-甲基苯基)乙炔（12d）是一种有效的COX-2抑制剂（IC(50)=0.32 microM），具有高COX-2选择性指数（SI>320），与参考化合物罗非昔布相当（COX-2 IC(50)=0.50 microM；COX-2 SI>200）。一项分子建模研究将（12d）对接在COX-2的结合位点，结果表明MeSO(2) COX-2药效基团位于靠近Val(523)的COX-2二级结合位点附近。1-(4-甲基磺酰基苯基)-2-(3-乙酰氧基苯基)乙炔（11f，COX-1 IC(50)=1.00 microM；COX-2 IC(50)=0.06 microM；COX-2 SI=16.7）和1-(3-甲基磺酰基苯基)-2-(3-乙酰氧基苯基)乙炔（12f，COX-1 IC(50)=6.5 microM；COX-2 IC(50)=0.05 microM；COX-2 SI=130）区域异构体表现出相当的COX-2抑制作用，相对于参考药物塞来昔布（COX-1 IC(50)=33.1 microM；COX-2 IC(50)=0.07 microM；COX-2 SI=472），其选择性COX-2选择性略低。最有效的抗炎剂1-(3-甲基磺酰基苯基)-2-(4-甲基苯基)乙炔（12d）在角叉菜胶诱导的大鼠爪肿胀试验中，给药后3小时表现出中等的口服抗炎活性（ED(50)=129 mg/kg），相对于参考药物塞来昔布（ED(50)=10.8 mg/kg）。获得的结构-活性数据表明，乙炔部分构成了一个合适的支架（模板），可用于设计具有选择性COX-2或双重COX-1/COX-2抑制活性的新型无环1,2-二芳基乙炔。
