title: Discovery of 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole: integrated drug-design and structure-activity relationships for orally potent, metabolically stable and potential-risk reduced novel non-peptide nociceptin/orphanin FQ receptor agonist as antianxiety drug.
abstract: Anxiety disorders, caused by continuous or acute stress or fear, have been highly prevailing psychiatric disorders. For the acute treatment of the disorders, benzodiazepines have been widely used despite having liabilities that limit their utility. Alternatively, endogenous nociceptin/orphanin FQ and nociceptin/orphanin FQ peptide receptor (or opioid-receptor-like-1 receptor) have important roles in the integration of emotional components, e.g. anxiolytic activity is the key behavioral action of nociceptin/orphanin FQ in brain. In our preceding study, various structurally novel 1,2-disubstituted benzimidazole derivatives were designed and synthesized as highly potent nociceptin/orphanin FQ peptide receptor selective full agonists in vitro with high or moderate nociceptin/orphanin FQ peptide receptor occupancy in the mice brain per os based on appropriate physicochemical properties for the oral brain activity [Hayashi et al. (2009) J Med Chem;52:610-625]. In the present study, drug design and structure-activity relationships for Vogel anticonflict activities in mice per os, metabolic stabilities in human liver microsome, CYP2D6 inhibitions, serum protein bindings, and human ether-a-go-go related gene binding affinities of novel nociceptin/orphanin FQ peptide receptor agonists were investigated. Through the series of coherent drug discovery studies, the strongest nociceptin/orphanin FQ peptide receptor agonist, 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole was designed and identified as a new-class orally potent anxiolytic with little side-effects, as significant findings.
authors.affiliation: Pfizer Global Research & Development Nagoya Laboratories, Pfizer Japan Inc, 5-2 Taketoyo, Aichi 470-2393, Japan. shigeo_hayashi@nifty.com
authors.forename: Shigeo
authors.initials: S
authors.lastname: Hayashi
authors.forename: Akiko
authors.initials: A
authors.lastname: Hirao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakamura
authors.forename: Kenzo
authors.initials: K
authors.lastname: Yamamura
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Mizuno
authors.forename: Hiroyo
authors.initials: H
authors.lastname: Yamashita
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002460:Cell Line; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D015221:Potassium Channels / Q000378:metabolism; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
chemical_list: C545294:1-(1-(1-methylcyclooctyl)-4-piperidinyl)-2-(3-piperidinyl)-1H-benzimidazole; D014151:Anti-Anxiety Agents; D001562:Benzimidazoles; D010880:Piperidines; D015221:Potassium Channels; D011957:Receptors, Opioid; D019389:Cytochrome P-450 CYP2D6; D000094942:Nociceptin Receptor