428871-69-6Relevant articles and documents
2-Cyclohexylcarbonylbenzimidazoles as potent, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonists
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
scheme or table, p. 3096 - 3099 (2010/03/31)
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.
