Optimization of benzimidazole series as opioid receptor-like 1 (ORL1) antagonists: SAR study directed toward improvement of selectivity over hERG activity

Kensuke Kobayashi; Tetsuya Kato; Izumi Yamamoto; Atsushi Shimizu; Sayaka Mizutani; Masanori Asai; Hiroshi Kawamoto; Satoru Ito; Takashi Yoshizumi; Mioko Hirayama; Satoshi Ozaki; Hisashi Ohta; Osamu Okamoto

doi:10.1016/j.bmcl.2009.04.022

Optimization of benzimidazole series as opioid receptor-like 1 (ORL1) antagonists: SAR study directed toward improvement of selectivity over hERG activity

Bioorg Med Chem Lett. 2009 Jun 1;19(11):3100-3. doi: 10.1016/j.bmcl.2009.04.022. Epub 2009 Apr 11.

Authors

Kensuke Kobayashi¹, Tetsuya Kato, Izumi Yamamoto, Atsushi Shimizu, Sayaka Mizutani, Masanori Asai, Hiroshi Kawamoto, Satoru Ito, Takashi Yoshizumi, Mioko Hirayama, Satoshi Ozaki, Hisashi Ohta, Osamu Okamoto

Affiliation

¹ Tsukuba Research Institute, Banyu Pharmaceutical Co, Ltd, Tsukuba, Ibaraki, Japan.

PMID: 19398200
DOI: 10.1016/j.bmcl.2009.04.022

Abstract

A structure-activity relationship (SAR) study on the benzimidazole series of opioid receptor-like 1 (ORL1) antagonists related to 1 is described. Optimization of 1 by introduction of a hydrophilic substituent into the thioether part resulted in identification of potent ORL1 antagonists with high selectivity over binding affinity for hERG and other opioid receptors.

MeSH terms

Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry*
Benzimidazoles / pharmacology
Cyclohexanes / chemical synthesis*
Cyclohexanes / pharmacology
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / metabolism*
Narcotic Antagonists*
Nociceptin Receptor
Receptors, Opioid / metabolism
Structure-Activity Relationship

Substances

Benzimidazoles
Cyclohexanes
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
Narcotic Antagonists
Receptors, Opioid
Nociceptin Receptor