Zarghi Afshin, Rao P N Praveen, Knaus Edward E
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
J Pharm Pharm Sci. 2007;10(2):159-67.
A group of 3,4-diaryl- 2(5H)furanones were synthesized to determine whether a N-acetylsulfonamido (SO2NHCOCH3) moiety could be used as a bioisosteric replacement for the traditional sulfonamide (SO2NH2) and methanesulfonyl (SO2CH3) COX-2 pharmacophores.
In vitro COX-1 and COX-2 isozyme inhibition studies were carried out to acquire structure activity relationship data with respect to the point of attachment of the Nacetylsulfonamide moiety at the para and metapositions of the C-4 phenyl ring in conjunction with a variety of substituents (H, F, Cl, Me, OMe) at the para position of the C-3 phenyl ring.
COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of COX-2 since no inhibition of COX-1 was observed at a concentration of 100 microM. The relative COX-2 potency, and COX-2 selectivity index, profiles for the C-4 para acetamidophenyl compounds, with respect to the C-3 phenyl parasubstituent was H > F > Cl. The point of attachment of the SO2NHCOCH3 substituent on the C-4 phenyl ring was a determinant of COX-2 potency, and COX-2 selectivity, where the relative activity profile was para acetylsulfonamido > meta acetylsulfonamido. 4-[4-(NAcetylsulfonamido) phenyl]-3-phenyl-2(5H)furanone was identified as a more potent (IC50 = 0.32 microM), and selective (S.I. > 313), COX-2 inhibitor than the parent reference compound rofecoxib (IC50 = 0.43 microM, S.I. > 232).
The SO2NHCOCH3 moiety i) is a novel COX-2 pharmacophore that also has the potential to serve as a prodrug moiety to the traditional SO2NH2 COX-2 pharmacophore, and ii) it could serve as a useful COX-2 pharmacophore to study the structure-function relationship of the COX-2 isozyme in view of its potential to acetylate the NH2 moiety of amino acid residues such as Gln192 or Arg513 that line the pocket of the secondary COX-2 binding site.
合成一组3,4 - 二芳基 - 2(5H)呋喃酮，以确定N - 乙酰磺酰胺基（SO2NHCOCH3）部分是否可作为传统磺酰胺基（SO2NH2）和甲磺酰基（SO2CH3）COX - 2药效基团的生物电子等排体替代物。
进行体外COX - 1和COX - 2同工酶抑制研究，以获取关于N - 乙酰磺酰胺部分在C - 4苯环的对位和间位连接点以及C - 3苯环对位各种取代基（H、F、Cl、Me、OMe）的构效关系数据。
COX - 1和COX - 2抑制研究表明，所有化合物都是COX - 2的选择性抑制剂，因为在100微摩尔浓度下未观察到对COX - 1的抑制作用。C - 4对乙酰氨基苯基化合物相对于C - 3苯环对取代基的相对COX - 2效力和COX - 2选择性指数概况为H > F > Cl。SO2NHCOCH3取代基在C - 4苯环上的连接点是COX - 2效力和COX - 2选择性的决定因素，其中相对活性概况为对乙酰磺酰胺基 > 间乙酰磺酰胺基。4 - [4 - （N - 乙酰磺酰胺基）苯基] - 3 - 苯基 - 2(5H)呋喃酮被鉴定为比母体参考化合物罗非昔布（IC50 = 0.43微摩尔，S.I. > 232）更有效（IC50 = 0.32微摩尔）和更具选择性（S.I. > 313）的COX - 2抑制剂。
SO2NHCOCH3部分i）是一种新型COX - 2药效基团，也有潜力作为传统SO2NH2 COX - 2药效基团的前药部分，并且ii）鉴于其有潜力乙酰化位于COX - 2二级结合位点口袋中的氨基酸残基（如Gln192或Arg513）的NH2部分，它可作为研究COX - 2同工酶结构功能关系的有用COX - 2药效基团。
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