title: 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines as mGluR2 positive allosteric modulators for the treatment of psychosis.
abstract: A novel series of mGluR2 positive allosteric modulators (PAMs), 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, is herein disclosed. Structure-activity relationship studies led to potent, selective mGluR2 PAMs with excellent pharmacokinetic profiles. A representative lead compound (+)-17e demonstrated dose-dependent inhibition of methamphetamine-induced hyperactivity and mescaline-induced scratching in mice, providing support for potential efficacy in treating psychosis.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United States. Lei.Zhang3@pfizer.com
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brodney
authors.forename: John
authors.initials: J
authors.lastname: Candler
authors.forename: Angela C
authors.initials: AC
authors.lastname: Doran
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Duplantier
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Efremov
authors.forename: Edel
authors.initials: E
authors.lastname: Evrard
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kraus
authors.forename: Alan H
authors.initials: AH
authors.lastname: Ganong
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Haas
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Hanks
authors.forename: Keith
authors.initials: K
authors.lastname: Jenza
authors.forename: John T
authors.initials: JT
authors.lastname: Lazzaro
authors.forename: Noha
authors.initials: N
authors.lastname: Maklad
authors.forename: Sheryl A
authors.initials: SA
authors.lastname: McCarthy
authors.forename: Weimin
authors.initials: W
authors.lastname: Qian
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Rogers
authors.forename: Melinda D
authors.initials: MD
authors.lastname: Rottas
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schmidt
authors.forename: Judith A
authors.initials: JA
authors.lastname: Siuciak
authors.forename: F David
authors.initials: FD
authors.lastname: Tingley
authors.forename: Andy Q
authors.initials: AQ
authors.lastname: Zhang
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D008694:Methamphetamine; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011487:Protein Conformation; D011869:Radioligand Assay; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C558743:1-methyl-2-((3-methyl-4-(4-trifluoromethyl-2-fluoro)phenyl)piperidin-1-ylmethyl)-1H-imidazo(4,5-b)pyridine; D014150:Antipsychotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007093:Imidazoles; D010880:Piperidines; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D008694:Methamphetamine