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

  • Bioorg Med Chem Lett. 2009 Jun 1;19(11):3096-9. doi: 10.1016/j.bmcl.2009.04.023.
Kensuke Kobayashi  1 ,  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
Affiliations
  • 1. Tsukuba Research Institute, Banyu Pharmaceutical Co, Ltd, Tsukuba, Ibaraki, Japan.
PMID: 19394217 DOI: 10.1016/j.bmcl.2009.04.023
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.