Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu1

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Manka, Jason T.^1,2  Rodriguez, Alice L.^1,2  Morrison, Ryan D.^1,2  Venable, Daryl F.^1,2  Cho, Hyekyung P.^1,2  Blobaum, Anna L.^1,2  Daniels, J. Scott^1,2  Niswender, Colleen M.^1,2  Conn, P. Jeffrey^1,2  Lindsley, Craig W.^1,2,3  Emmitte, Kyle A.^1,2,3 

[1] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

关键词: Glutamate;    GPCR;    mGlu(1);    Allosteric modulator;    CNS;    Octahydropyrrolo[3,4-c]pyrrole;   

DOI  :  10.1016/j.bmcl.2013.07.029

来源: Elsevier

【 摘 要 】

Development of SAR in an octahydropyrrolo[3,4-c]pyrrole series of negative allosteric modulators of mGlu(1) using a functional cell-based assay is described in this Letter. The octahydropyrrolo[3,4-c]pyrrole scaffold was chosen as an isosteric replacement for the piperazine ring found in the initial hit compound. Characterization of selected compounds in protein binding assays was used to identify the most promising analogs, which were then profiled in P450 inhibition assays in order to further assess the potential for drug-likeness within this series of compounds. (C) 2013 Elsevier Ltd. All rights reserved.

【 授权许可】

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