TY - JOUR
T1 - Isomeric methoxy analogs of nimesulide for development of brain cyclooxygense-2 (COX-2)-targeted imaging agents
T2 - Synthesis, in vitro COX-2-inhibitory potency, and cellular transport properties
AU - Yamamoto, Yumi
AU - Hisa, Takuya
AU - Arai, Jun
AU - Saito, Yohei
AU - Yamamoto, Fumihiko
AU - Mukai, Takahiro
AU - Ohshima, Takashi
AU - Maeda, Minoru
AU - Ohkubo, Yasuhito
N1 - Funding Information:
This research was supported partly by a Grant-in-Aid for Young Scientists from the Japan Society for the Promotion of Science (Nos. 24791331 , 26861015 ). The authors acknowledge Kaori Morimoto Ph.D. lecturer of Tohoku Pharmaceutical University, for valuable discussion on the transport assay. We greatly appreciate Ms. Asuka Okayasu, Ms. Akiyo Oiwa and Ms. Miho Takeda for their technical assistance.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - 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 P7.4 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.
AB - 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 P7.4 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.
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U2 - 10.1016/j.bmc.2015.10.007
DO - 10.1016/j.bmc.2015.10.007
M3 - Article
C2 - 26455657
AN - SCOPUS:84946109684
VL - 23
SP - 6807
EP - 6814
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 21
ER -