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Dihydrothiazolopyridone Derivatives as a Novel Family of Positive Allosteric Modulators of the Metabotropic Glutamate 5 (mGlu5) Receptor

Starting from a singleton chromanone high throughput screening (HTS) hit, we describe a focused medicinal chemistry optimization effort leading to the identification of a novel series of phenoxymethyl-dihydrothiazolopyridone derivatives as selective positive allosteric modulators (PAMs) of the metabotropic glutamate 5 (mGlu5) receptor. These dihydrothiazolopyridones potentiate receptor responses in recombinant systems. In vitro and in vivo drug metabolism and pharmacokinetic (DMPK) evaluation allowed us to select compound 16a for its assessment in a preclinical animal screen of possible antipsychotic activity. 16a was able to reverse amphetamine-induced hyperlocomotion in rats in a dose-dependent manner without showing any significant motor impairment or overt neurological side effects at comparable doses. Evolution of our medicinal chemistry program, structure activity, and properties relationships (SAR and SPR) analysis as well as a detailed profile for optimized mGlu5 receptor PAM 16a are described.

Authors:   José Manuel Bartolomé-Nebreda; Susana Conde-Ceide; Francisca Delgado; Laura Iturrino; Joaquín Pastor; Miguel Ángel Pena; Andrés A. Trabanco; Gary Tresadern; Carola M. Wassvik; Shaun R. Stauffer; Satyawan Jadhav; Kiran Gogi; Paige N. Vinson; Meredith J. Noetzel; Emily Days; C. David Weaver; Craig W. Lindsley; Colleen M. Niswender; Carrie K. Jones; P. Jeffrey Conn; Frederik Rombouts; Hilde Lavreysen; Gregor J. Macdonald; Claire Mackie; Thomas Steckler
Journal:   Journal of Medicinal Chemistry
Year:   2013
DOI:   10.1021/jm400650w
Publication date:   04-Sep-2013
Facts, background information, dossiers
  • medicinal chemistry
  • pharmacokinetics
  • Pam
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