Azetidinyl oxadiazoles as potent mGluR5 positive allosteric modulators

被引：12
|
作者：
Packiarajan, Mathivanan [1 ]
Ferreira, Christine G. Mazza [1 ]
Hong, Sang-Phyo [1 ]
White, Andrew D. [1 ]
Chandrasena, Gamini [1 ]
Pu, Xiaosui [2 ]
Brodbeck, Robbin M. [2 ]
Robichaud, Albert J. [1 ]
机构：
[1] Lundbeck Res USA, Chem & Pharmacokinet Sci, Paramus, NJ 07652 USA
[2] Lundbeck Res USA, Dis Biol Unit, Synapt Transmiss, Paramus, NJ 07652 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 20期
关键词：
mGluR5 positive allosteric modulators; Azetidinyl oxadiazoles; Azetidinyl N-cyclohexyl carboxamides and carbamates; Azetidinyl N-sulfonamides; PAM to NAM switching; METABOTROPIC GLUTAMATE RECEPTORS; METHYL-D-ASPARTATE; IN-VIVO; MOLECULAR CHARACTERIZATION; FUNCTIONAL INTERACTION; ANTIPSYCHOTIC-LIKE; SUBTYPE; DISCOVERY; RAT; PHARMACOLOGY;
D O I：
10.1016/j.bmcl.2012.08.044
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A novel series of aryl azetidinyl oxadiazoles are identified as mGluR5 positive allosteric modulators (PAMs) with improved physico-chemical properties. N-substituted cyclohexyl and exo-norbornyl carboxamides, and carbamate analogs of azetidines are moderate to potent mGluR5 PAMs. The aryl, lower alkyl carboxamides analogs and sulfonamide analogs of azetidines are moderate mGluR5 negative allosteric modulators (NAMs). In the aryl oxadiazole moiety, substituents such as fluoro, chloro and methyl are well tolerated at the meta position while para substituents led to either inactive compounds or NAMs. A tight pharmacophore and subtle 'PAM to NAM switching' with close analogs makes the optimization of the series extremely challenging. (c) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码：6469 / 6474
页数：6
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