Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1376620 | Bioorganic & Medicinal Chemistry Letters | 2008 | 4 Pages |
Following the discovery of 5-chloro-6-[piperazin-1-yl]-1H-benzimidazole as a novel pharmacophore for potent and selective ORL1 antagonist activity, optimization of this new lead by introduction of a methyl substitution on the piperazine ring resulted in a highly potent and selective, orally available, and brain penetrable ORL1 antagonist, 2-(tert-butylthio)-5-chloro-6-[(2R)-4-(2-hydroxyethyl)-2-methylpiperazin-1-yl]-1H-benzimidazole. Stereochemistry of the methyl substituent on the piperazine ring to control the functional activity of other opioid receptors is also described.
Graphical abstractA novel ORL1-selective antagonist with oral bioavailability and brain penetrability, 2-(tert-butylthio)-5-chloro-6-[(2R)-4-(2-hydroxyethyl)-2-methylpiperazin-1-yl]-1H-benzimidazole, was identified in a 5-chloro-6-[piperazin-1-yl]-1H-benzimidazole series.Figure optionsDownload full-size imageDownload as PowerPoint slide