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Acyl dihydropyrazolo[1,5-a]pyrimidinones as metabotropic glutamate receptor 5 positive allosteric modulators.
Malosh, Chrysa; Turlington, Mark; Bridges, Thomas M; Rook, Jerri M; Noetzel, Meredith J; Vinson, Paige N; Steckler, Thomas; Lavreysen, Hilde; Mackie, Claire; Bartolomé-Nebreda, José M; Conde-Ceide, Susana; Martínez-Viturro, Carlos M; Piedrafita, María; Sánchez-Casado, M Rosa; Macdonald, Gregor J; Daniels, J Scott; Jones, Carrie K; Niswender, Colleen M; Conn, P Jeffrey; Lindsley, Craig W; Stauffer, Shaun R.
Afiliación
  • Malosh C; 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, U
  • Turlington M; 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, U
  • Bridges TM; 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, U
  • Rook JM; 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, U
  • Noetzel MJ; 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, U
  • Vinson PN; 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, U
  • Steckler T; Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • Lavreysen H; Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • Mackie C; Discovery Sciences ADME/Tox, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • Bartolomé-Nebreda JM; Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
  • Conde-Ceide S; Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
  • Martínez-Viturro CM; Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
  • Piedrafita M; Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
  • Sánchez-Casado MR; Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
  • Macdonald GJ; Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • Daniels JS; 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, U
  • Jones CK; 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, U
  • Niswender CM; 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, U
  • Conn PJ; 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, U
  • Lindsley CW; 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, U
  • Stauffer SR; 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, U
Bioorg Med Chem Lett ; 25(22): 5115-20, 2015 Nov 15.
Article en En | MEDLINE | ID: mdl-26475522
We report the optimization of a series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from an acyl dihydropyrazolo[1,5-a]pyrimidinone class. Investigation of exocyclic amide transpositions with this unique 5,6-bicyclic core were conducted in attempt to modulate physicochemical properties and identify a suitable backup candidate with a reduced half-life. A potent and selective PAM, 1-(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)ethanone (9a, VU0462807), was identified with superior solubility and efficacy in the acute amphetamine-induced hyperlocomotion (AHL) rat model with a minimum effective dose of 3mg/kg. Attempts to mitigate oxidative metabolism of the western phenoxy of 9a through extensive modification and profiling are described.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Pirimidinas / Pirimidinonas / Encéfalo / Receptor del Glutamato Metabotropico 5 Límite: Animals / Humans / Male Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Pirimidinas / Pirimidinonas / Encéfalo / Receptor del Glutamato Metabotropico 5 Límite: Animals / Humans / Male Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2015 Tipo del documento: Article Pais de publicación: Reino Unido