Design, synthesis, and structure-activity relationship study of a novel class of ORL1 receptor antagonists based on N-biarylmethyl spiropiperidine.
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.
Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan. takashi_yoshizumi@merck.com
Takashi
T
Yoshizumi
Hiroshi
H
Miyazoe
Hirokatsu
H
Ito
Tomohiro
T
Tsujita
Hirobumi
H
Takahashi
Masanori
M
Asai
Satoshi
S
Ozaki
Hisashi
H
Ohta
Osamu
O
Okamoto
D001667:Binding, Competitive; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D009292:Narcotic Antagonists; D010880:Piperidines / Q000737:chemistry*; D011485:Protein Binding; D011957:Receptors, Opioid; D013141:Spiro Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; D013141:Spiro Compounds; C032727:piperidine; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human