Bioorganic and Medicinal Chemistry Letters p. 3096 - 3099 (2009)
Update date:2022-08-02
Topics:
Kobayashi, Kensuke
Uchiyama, Minaho
Takahashi, Hirobumi
Kawamoto, Hiroshi
Ito, Satoru
Yoshizumi, Takashi
Nakashima, Hiroshi
Kato, Tetsuya
Shimizu, Atsushi
Yamamoto, Izumi
Asai, Masanori
Miyazoe, Hiroshi
Ohno, Akio
Hirayama, Mioko
Ozaki, Satoshi
Tani, Takeshi
Ishii, Yasuyuki
Tanaka, Takeshi
Mochidome, Takanobu
Tadano, Kiyoshi
Fukuroda, Takahiro
Ohta, Hisashi
Okamoto, Osamu
The synthesis and biological evaluation of new potent opioid receptor-like 1 (ORL1) antagonists are presented. Conversion of the thioether linkage of the prototype [It is reported prior to this communication as a consecutive series.: Kobayashi, K.; Kato, T.; Yamamoto, I.; Shimizu, A.; Mizutani, S.; Asai, M.; Kawamoto, H.; Ito, S.; Yoshizumi, T.; Hirayama, M.; Ozaki, S.; Ohta, H.; Okamoto, O. Bioorg. Med. Chem. Lett., in press] to the carbonyl linker effectively reduces susceptibility to P-glycoprotein (P-gp) efflux. This finding led to the identification of 2-cyclohexylcarbonylbenzimizole analogue 7c, which exhibited potent ORL1 activity, excellent selectivity over other receptors and ion channels, and poor susceptibility to P-gp. Compound 7c also showed satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Furthermore, 7c showed good in vivo antagonism. Hence, 7c was selected as a clinical candidate for a brain-penetrable ORL1 antagonist.
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