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

被引：6

作者：

Ellard, John M. ^{[1
]}

Madin, Andrew ^{[1
]}

Philps, Oliver ^{[1
]}

Hopkin, Mark ^{[1
]}

Henderson, Scott ^{[1
]}

Birch, Louise ^{[1
]}

O'Connor, Desmond ^{[3
]}

Arai, Tohru ^{[4
]}

Takase, Kazuma ^{[5
]}

Morgan, Louise ^{[2
]}

Reynolds, David ^{[2
]}

Talma, Sonia ^{[2
]}

Howley, Eimear ^{[2
]}

Powney, Ben ^{[2
]}

Payne, Andrew H. ^{[1
]}

Hall, Adrian ^{[1
]}

Gartlon, Jane E. ^{[2
]}

Dawson, Lee A. ^{[2
]}

Castro, Luis ^{[1
]}

Atkinson, Peter J. ^{[2
]}

机构：

[1] Eisai Ltd, Med Chem Neurosci Prod Creat Unit, European Knowledge Ctr, Hatfield AL10 9SN, Herts, England

[2] Eisai Ltd, Pharmacol Neurosci Prod Creat Unit, European Knowledge Ctr, Hatfield AL10 9SN, Herts, England

[3] Eisai Ltd, European Knowledge Ctr, Neurosci Prod Creat Unit, DMPK, Hatfield AL10 9SN, Herts, England

[4] Eisai & Co Ltd, Eisai Prod Creat Syst, Next Generat Syst Core Funct Unit, Tsukuba, Ibaraki 3002635, Japan

[5] Eisai & Co Ltd, Eisai Prod Creat Syst, Biomarker & Personalized Med Core Funct Unit, Tsukuba, Ibaraki 3002635, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 24期

关键词：

Metabotropic glutamate receptor 5 (mGlu5); Positive allosteric modulator (PAM); Cognition; Tetrahydrobenzotriazole; DISCOVERY; MGLUR5;

D O I：

10.1016/j.bmcl.2015.10.050

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：5792 / 5796

页数：5

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