Dihydrothiazolopyridone Derivatives as a Novel Family of Positive Allosteric Modulators of the Metabotropic Glutamate 5 (mGlu5) Receptor
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- 作者：Jos茅 Manuel Bartolom茅-Nebreda ; Susana Conde-Ceide ; Francisca Delgado ; Laura Iturrino ; Joaqu铆n Pastor ; Miguel 脕ngel Pena ; Andr茅s 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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：September 26, 2013
- 年：2013
- 卷：56
- 期：18
- 页码：7243-7259
- 全文大小：708K
- 年卷期：v.56,no.18(September 26, 2013)
- ISSN：1520-4804
文摘
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.