title: Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency.
abstract: We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of non-amide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly potent and selective PAM, 2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (11, VU0462054), bearing a simple ketone moiety, was identified (LE=0.52, LELP=3.2). In addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising lead properties and exploration of alternative core heterocycles, linkers, and ketone replacements, oxidative metabolism and in vivo clearance remained problematic for the series.
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors: Mark
authors: M
authors: Turlington
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: Meredith J
authors: MJ
authors: Noetzel
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: Thomas M
authors: TM
authors: Bridges
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: Paige N
authors: PN
authors: Vinson
authors: Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Thomas
authors: T
authors: Steckler
authors: Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Hilde
authors: H
authors: Lavreysen
authors: Discovery Sciences ADME/Tox, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Claire
authors: C
authors: Mackie
authors: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
authors: José M
authors: JM
authors: Bartolomé-Nebreda
authors: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
authors: Susana
authors: S
authors: Conde-Ceide
authors: Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
authors: Han Min
authors: HM
authors: Tong
authors: Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors: Gregor J
authors: GJ
authors: Macdonald
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: J Scott
authors: JS
authors: Daniels
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: Carrie K
authors: CK
authors: Jones
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: Colleen M
authors: CM
authors: Niswender
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
authors: P Jeffrey
authors: PJ
authors: Conn
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors: Craig W
authors: CW
authors: Lindsley
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: shaun.stauffer@vanderbilt.edu.
authors: Shaun R
authors: SR
authors: Stauffer
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D010881:Piperidones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C000595769:2-(phenoxymethyl)-6,7-dihydropyrazolo(1,5-a)pyridin-4(5H)-one; D008024:Ligands; D010881:Piperidones; D011720:Pyrazoles; D064529:Receptor, Metabotropic Glutamate 5
keywords: Metabotropic glutamate receptor 5 (mGlu(5)); Positive allosteric modulator (PAM)