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

• Published in: Bioorganic & medicinal chemistry Vol. 23; no. 21; pp. 6807 - 6814
• Main Authors: Yamamoto, Yumi, Hisa, Takuya, Arai, Jun, Saito, Yohei, Yamamoto, Fumihiko, Mukai, Takahiro, Ohshima, Takashi, Maeda, Minoru, Ohkubo, Yasuhito
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.11.2015; Elsevier
• Subjects: Biochemistry & Molecular Biology; Brain - enzymology; Caco-2 Cells; Catalytic Domain; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Contrast Media - chemical synthesis; Contrast Media - chemistry; Contrast Media - metabolism; COX-2; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - metabolism; Humans; Isomerism; Life Sciences & Biomedicine; Methoxy substituted analog; Molecular Conformation; Molecular Dynamics Simulation; Nimesulide; Pharmacology & Pharmacy; Physical Sciences; Protein Binding; Science & Technology; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - metabolism; Methoxy substituted analog; Caco-2 cells; Nimesulide; COX-2; VIVO EVALUATION; PET TRACER; DOCKING; CACO-2; BARRIER; P-GLYCOPROTEIN; COX-2 EXPRESSION; POSITRON-EMISSION-TOMOGRAPHY; RADIOSYNTHESIS; INHIBITORS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.10.007

[Display omitted] 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 logP7.4 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.