Referenced in: none

Automatically associated channels: Kir2.3

Title: 2-Cyclohexylcarbonylbenzimidazoles as potent, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonists.

Authors: Kensuke Kobayashi, Minaho Uchiyama, Hirobumi Takahashi, Hiroshi Kawamoto, Satoru Ito, Takashi Yoshizumi, Hiroshi Nakashima, Tetsuya Kato, Atsushi Shimizu, Izumi Yamamoto, Masanori Asai, Hiroshi Miyazoe, Akio Ohno, Mioko Hirayama, Satoshi Ozaki, Takeshi Tani, Yasuyuki Ishii, Takeshi Tanaka, Takanobu Mochidome, Kiyoshi Tadano, Takahiro Fukuroda, Hisashi Ohta, Osamu Okamoto

Journal, date & volume: Bioorg. Med. Chem. Lett., 2009 Jun 1 , 19, 3096-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19394217

Abstract
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.