Masaya Hashimoto

Novel ORL1-selective antagonists with oral bioavailability and brain penetrability

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.

Identification of novel benzimidazole series of potent and selective ORL1 antagonists

Structure-activity studies on benzimidazole lead 1 obtained from library screening led to the discovery of potent and selective ORL1 antagonist 28, 5-chloro-2-[(1-ethyl-1-methylpropyl)thio]-6-[4-(2-hydroxyethyl)piperazin-1-yl]-1H-benzimidazole, which is structurally distinct from conventional non-peptide antagonists known to date.