title: Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: design, synthesis, and structure-activity relationships.
abstract: Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C- and Aδ-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects.
authors.affiliation: Pfizer Global Research & Development Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Hayashi
authors.forename: Eriko
authors.initials: E
authors.lastname: Nakata
authors.forename: Asato
authors.initials: A
authors.lastname: Morita
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Mizuno
authors.forename: Kenzo
authors.initials: K
authors.lastname: Yamamura
authors.forename: Aki
authors.initials: A
authors.lastname: Kato
authors.forename: Katsuyo
authors.initials: K
authors.lastname: Ohashi
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy*; D011758:Pyrroles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
chemical_list: C555728:(1-(4-(2-(hexahydropyrrolo(3,4-c)pyrrol-2(1H)-yl)-1H-benzimidazol-1-yl)piperidin-1-yl)cyclooctyl)methanol; D000700:Analgesics; D001562:Benzimidazoles; D011758:Pyrroles; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor