title: Discovery of 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as positive allosteric modulators of metabotropic glutamate subtype-2 (mGlu2) receptors with efficacy in a preclinical model of psychosis.
abstract: Optimization of a benzimidazolone template for potency and physical properties revealed 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as a key template on which to develop a new series of mGlu2 positive allosteric modulators (PAMs). Systematic investigation of aryl-SAR led to the identification of compound 27 as a potent and highly selective mGlu2 PAM with sufficient pharmacokinetics to advance to preclinical models of psychosis. Gratifyingly, compound 27 showed full efficacy in the PCP- and MK-801-induced hyperlocomotion assay in rats at CSF concentrations consistent with mGlu2 PAM potency.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Layton
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Reif
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hartingh
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rodzinak
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Vadim
authors.initials: V
authors.lastname: Dudkin
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Ken
authors.initials: K
authors.lastname: Arrington
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelly
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.affiliation: Department of In Vitro Sciences, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Julie A
authors.initials: JA
authors.lastname: O'Brien
authors.affiliation: Department of Psychiatry Research, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Magliaro
authors.affiliation: Department of Central Pharmacology, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.affiliation: Department of Central Pharmacology, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Huszar
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Fillgrove
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Cuyue
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Yuhsin
authors.initials: Y
authors.lastname: Kuo
authors.affiliation: Department of Psychiatry Research, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, United States.
authors.forename: Marlene A
authors.initials: MA
authors.lastname: Jacobson
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D007093:Imidazoles / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D008124:Locomotion / Q000187:drug effects; D011485:Protein Binding; D011618:Psychotic Disorders / Q000188:drug therapy / Q000473:pathology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011728:Pyridones / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D011725:Pyridines; D011728:Pyridones; D018094:Receptors, Metabotropic Glutamate; C000600672:imidazo(4,5-b)pyridine; C108822:metabotropic glutamate receptor 2
keywords: Metabotropic glutamate receptor; Positive allosteric modulator; Schizophrenia; mGlu2 PAM