N-Acyl-N′-arylpiperazines as negative allosteric modulators of mGlu1: Identification of VU0469650, a potent and selective tool compound with CNS exposure in rats

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Lovell, Kimberly M.^1,2  Felts, Andrew S.^1,2  Rodriguez, Alice L.^1,2  Venable, Daryl F.^1,2  Cho, Hyekyung P.^1,2  Morrison, Ryan D.^1,2  Byers, Frank W.^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;    Piperazine;   

DOI  :  10.1016/j.bmcl.2013.05.020

来源: Elsevier

【 摘 要 】

Development of SAR in an N-acyl-N'-arylpiperazine series of negative allosteric modulators of mGlu(1) using a functional cell-based assay is described in this Letter. Characterization of selected compounds in protein binding assays was used to aid in selecting VU0469650 for further profiling in ancillary pharmacology assays and pharmacokinetic studies. VU0469650 demonstrated an excellent selectivity profile and good exposure in both plasma and brain samples following intraperitoneal dosing in rats. (C) 2013 Elsevier Ltd. All rights reserved.

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