3-Cyano-5-fluoro-N-arylbenzamides as negative allosteric modulators of mGlu5: Identification of easily prepared tool compounds with CNS exposure in rats

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

Felts, Andrew S.^1,2  Lindsley, Stacey R.^1,2  Lamb, Jeffrey P.^1,2  Rodriguez, Alice L.^1,2  Menon, Usha N.^1,2  Jadhav, Satyawan^1,2  Jones, Carrie K.^1,2,3,4  Conn, P. Jeffrey^1,2  Lindsley, Craig W.^1,2,3  Emmitte, Kyle A.^1,2 

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

[2] Vanderbilt Univ, Med Ctr, Vanderbilt Program Drug Discovery, Nashville, TN 37232 USA

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

[4] Tennesse Valley Healthcare Syst, US Dept Vet Affairs, Nashville, TN 37212 USA

关键词: mGlu5;    GPCR;    Allosteric modulator;    CNS;    GERD;    Fragile X syndrome;    Addiction;    PD-LID;   

DOI  :  10.1016/j.bmcl.2010.06.064

来源: Elsevier

【 摘 要 】

Development of SAR in a 3-cyano-5-fluoro-N-arylbenzamide series of non-competitive antagonists of mGlu(5) using a functional cell-based assay is described in this Letter. Further characterization of selected potent compounds in in vitro assays designed to measure their metabolic stability and protein binding is also presented. Subsequent evaluation of two new compounds in pharmacokinetic studies using intraperitoneal dosing in rats demonstrated good exposure in both plasma and brain samples. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

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