Design, synthesis, and structure-activity relationship study of a novel class of ORL1 receptor antagonists based on N-biarylmethyl spiropiperidine

Takashi Yoshizumi; Hiroshi Miyazoe; Hirokatsu Ito; Tomohiro Tsujita; Hirobumi Takahashi; Masanori Asai; Satoshi Ozaki; Hisashi Ohta; Osamu Okamoto

doi:10.1016/j.bmcl.2008.05.036

Design, synthesis, and structure-activity relationship study of a novel class of ORL1 receptor antagonists based on N-biarylmethyl spiropiperidine

Bioorg Med Chem Lett. 2008 Jul 1;18(13):3778-82. doi: 10.1016/j.bmcl.2008.05.036. Epub 2008 May 16.

Authors

Takashi Yoshizumi¹, Hiroshi Miyazoe, Hirokatsu Ito, Tomohiro Tsujita, Hirobumi Takahashi, Masanori Asai, Satoshi Ozaki, Hisashi Ohta, Osamu Okamoto

Affiliation

¹ Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan. takashi_yoshizumi@merck.com

PMID: 18515099
DOI: 10.1016/j.bmcl.2008.05.036

Abstract

Based on reported structures, a focused library of biarylmethyl bound to the nitrogen atom of spiropiperidine was designed. Systematic modifications allowed the discovery of a synthetically feasible and highly potent ORL1 antagonist 37, 1'-{[1-(3-chloropyridin-2-yl)-1H-pyrazol-4-yl]methyl}-3H-spiro[2-benzofuran-1,4'-piperidine], which exhibits excellent selectivity to mu, kappa, and human ether-a-go-go related gene potassium channel.

MeSH terms

Binding, Competitive
Chemistry, Pharmaceutical / methods*
Drug Design
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / metabolism
Humans
Inhibitory Concentration 50
Models, Chemical
Molecular Conformation
Molecular Structure
Narcotic Antagonists*
Nociceptin Receptor
Piperidines / chemistry*
Protein Binding
Receptors, Opioid
Spiro Compounds / chemistry*
Structure-Activity Relationship

Substances

ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
KCNH2 protein, human
Narcotic Antagonists
Piperidines
Receptors, Opioid
Spiro Compounds
piperidine
Nociceptin Receptor
OPRL1 protein, human