Identification and optimisation of a series of tetrahydrobenzotriazoles as metabotropic glutamate receptor 5-selective positive allosteric modulators that improve performance in a preclinical model of cognition. Issue 24 (15th December 2015)

• Record Type: Journal Article
• Authors: Ellard, John M.; Madin, Andrew; Philps, Oliver; Hopkin, Mark; Henderson, Scott; Birch, Louise; O'Connor, Desmond; Arai, Tohru; Takase, Kazuma; Morgan, Louise; Reynolds, David; Talma, Sonia; Howley, Eimear; Powney, Ben; Payne, Andrew H.; Hall, Adrian; Gartlon, Jane E.; Dawson, Lee A.; Castro, Luis; Atkinson, Peter J.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 24(2015)
• Page Start: 5792
• Page End: 5796
• Publication Date: 2015-12-15
• Subjects: Metabotropic glutamate receptor 5 (mGlu5) -- Positive allosteric modulator (PAM) -- Cognition -- Tetrahydrobenzotriazole; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.10.050
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result29 was identified as a suitable compound for progression to in vivo safety evaluation.