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

作者：Manuel Bartolome Nebreda Jose; Conde Ceide Susana; Delgado Francisca; Iturrino Laura; Pastor Joaquin; Angel Pena Miguel; Trabanco Andres A; Tresadern Gary; Wassvik Carola M; Stauffer Shaun R; Jadhav Satyawan; Gogi Kiran; Vinson Paige N; Noetzel Meredith J; Days Emily; Weaver C David; Lindsley Craig W; Niswender Colleen M; Jones Carrie K; Conn P Jeffrey; Rombouts Frederik; Lavreysen Hilde; Macdonald Gregor J; Mackie Claire; Steckler Thomas

来源：Journal of Medicinal Chemistry, 2013, 56(18): 7243-7259.

DOI：10.1021/jm400650w

Starting from a singleton chromanone high throughput screening (FITS) 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 (mGlu(5)) 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 mGlu(5) receptor PAM 16a are described.

• 出版日期2013-9-26