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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.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Dec 15; Vol. 25 (24), pp. 5792-6. Date of Electronic Publication: 2015 Oct 17. - Publication Year :
- 2015
-
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 of 29 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 result 29 was identified as a suitable compound for progression to in vivo safety evaluation.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Allosteric Regulation drug effects
Animals
Antipsychotic Agents metabolism
Antipsychotic Agents pharmacology
Astrocytes cytology
Astrocytes drug effects
Astrocytes metabolism
Cognition drug effects
Disease Models, Animal
Drug Evaluation, Preclinical
Half-Life
Humans
Microsomes metabolism
Rats
Receptor, Metabotropic Glutamate 5 metabolism
Structure-Activity Relationship
Triazoles metabolism
Triazoles pharmacology
Antipsychotic Agents chemistry
Receptor, Metabotropic Glutamate 5 antagonists & inhibitors
Triazoles chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 25
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 26531152
- Full Text :
- https://doi.org/10.1016/j.bmcl.2015.10.050