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.

Autor: Ellard JM; Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Madin A; Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Philps O; Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Hopkin M; Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Henderson S; Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Birch L; Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., O'Connor D; DMPK, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Arai T; Next Generation Systems Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635 Japan., Takase K; Biomarker and Personalized Medicine Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635 Japan., Morgan L; Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Reynolds D; Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Talma S; Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Howley E; Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Powney B; Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Payne AH; Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Hall A; Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Gartlon JE; Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Dawson LA; Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Castro L; Medicinal Chemistry, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK., Atkinson PJ; Pharmacology, Neuroscience Product Creation Unit, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK. Electronic address: Peter_Atkinson@eisai.net.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Dec 15; Vol. 25 (24), pp. 5792-6. Date of Electronic Publication: 2015 Oct 17.
DOI: 10.1016/j.bmcl.2015.10.050
Abstrakt: 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.
(Copyright © 2015 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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