Isomeric iodinated analogs of nimesulide: Synthesis, physicochemical characterization, cyclooxygenase-2 inhibitory activity, and transport across Caco-2 cells.
Isomeric iodinated derivatives of nimesulide, with an iodine substituent on the phenoxy ring, were prepared with the aim of identifying potential candidate compounds for the development of imaging agents targeting cyclooxygenase-2 (COX-2) in the brain. Both the experimental logP7.4 and pKa values for these iodinated analogs were in the acceptable range for passive brain penetration. The para-iodo-substituted analog was a more potent and selective COX-2 inhibitor than nimesulide, with a potency that was comparable to the reference drug, celecoxib. Iodination at the ortho- or meta-position of the phenoxy ring was associated with a substantial loss of COX-2 inhibitory activity. Transport studies across Caco-2 cell monolayers in the presence and absence of a P-glycoprotein (P-gp) inhibitor, verapamil, indicated that the para-iodo-substituted analog was not a P-gp transport substrate; this feature is a prerequisite for potential in vivo brain imaging compounds. The para-iodo-substituted analog of nimesulide appears to be an attractive candidate for the development of radioiodine-labeled tracers for in vivo brain imaging of COX-2 levels.
Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic address: yumi-y@tohoku-mpu.ac.jp.
Yumi
Y
Yamamoto
Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Jun
J
Arai
Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Takuya
T
Hisa
Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Yohei
Y
Saito
Kobe Pharmaceutical University, 4-19-1 Motoyama Kitamachi, Higashinada-ku, Kobe 658-8558, Japan.
Takahiro
T
Mukai
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Takashi
T
Ohshima
Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
Minoru
M
Maeda
Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Fumihiko
F
Yamamoto
D000818:Animals; D001921:Brain / Q000378:metabolism; D018938:Caco-2 Cells; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007536:Isomerism; D051379:Mice; D008807:Mice, Inbred BALB C; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D013449:Sulfonamides; C012655:nimesulide
Blood–brain barrier; COX-2; Caco-2 cell monolayers; Iodine; Lipophilicity; Nimesulide