title: 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.
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.
authors.affiliation: Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Ellard
authors.affiliation: Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Madin
authors.affiliation: Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Philps
authors.affiliation: Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Hopkin
authors.affiliation: Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Scott
authors.initials: S
authors.lastname: Henderson
authors.affiliation: Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Birch
authors.affiliation: DMPK, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Desmond
authors.initials: D
authors.lastname: O'Connor
authors.affiliation: Next Generation Systems Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635 Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Arai
authors.affiliation: Biomarker and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635 Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Takase
authors.affiliation: Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Morgan
authors.affiliation: Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: David
authors.initials: D
authors.lastname: Reynolds
authors.affiliation: Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Sonia
authors.initials: S
authors.lastname: Talma
authors.affiliation: Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Eimear
authors.initials: E
authors.lastname: Howley
authors.affiliation: Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Powney
authors.affiliation: Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Payne
authors.affiliation: Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Hall
authors.affiliation: Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Gartlon
authors.affiliation: Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Dawson
authors.affiliation: Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK.
authors.forename: Luis
authors.initials: L
authors.lastname: Castro
authors.affiliation: Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK. Electronic address: Peter_Atkinson@eisai.net.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Atkinson
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006801:Humans; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D064529:Receptor, Metabotropic Glutamate 5; D014230:Triazoles; C012771:benzotriazole
keywords: Cognition; Metabotropic glutamate receptor 5 (mGlu5); Positive allosteric modulator (PAM); Tetrahydrobenzotriazole