Isomeric methoxy analogs of nimesulide for development of brain cyclooxygense-2 (COX-2)-targeted imaging agents: Synthesis, in vitro COX-2-inhibitory potency, and cellular transport properties. Issue 21 (1st November 2015)

• Record Type: Journal Article
• Authors: Yamamoto, Yumi; Hisa, Takuya; Arai, Jun; Saito, Yohei; Yamamoto, Fumihiko; Mukai, Takahiro; Ohshima, Takashi; Maeda, Minoru; Ohkubo, Yasuhito
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 21(2015)
• Page Start: 6807
• Page End: 6814
• Publication Date: 2015-11-01
• Subjects: Nimesulide -- Methoxy substituted analog -- COX-2 -- Caco-2 cells; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.10.007
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Nimesulide analogs bearing a methoxy substituent either at the ortho -, meta - or para -position on the phenyl ring, were designed, synthesized, and evaluated for potential as radioligands for brain cyclooxygenase-2 (COX-2) imaging. The synthesis of nimesulide and regioisomeric methoxy analogs was based on the copper-mediated arylation of phenolic derivatives for the construction of diaryl ethers. These isomeric methoxy analogs displayed lipophilicity similar to that of nimesulide itself, as evidenced by their HPLC log P 7.4 values. In vitro inhibition studies using a colorimetric COX (ovine) inhibitor-screening assay demonstrated that the para -methoxy substituted analog retains the inhibition ability and selectivity observed for parent nimesulide toward COX-2 enzyme, whereas the meta - and ortho -methoxy substituents detrimentally affected COX-2-inhibition activity, which was further supported by molecular docking studies. Bidirectional transport cellular studies using Caco-2 cell culture model in the presence of the P-glycoprotein (P-gp) inhibitor, verapamil, showed that P-gp did not have a significant effect on the efflux of the para -methoxy substituted analog. Further investigations using the radiolabeled form of the para -methoxy substituted analog is warranted for in vivo characterization.