Discovery of molecular switches within the ADX-47273 mGlu5 PAM scaffold that modulate modes of pharmacology to afford potent mGlu5 NAMs, PAMs and partial antagonists

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Lamb, Jeffrey P.^1,3  Engers, Darren W.^1,3,4  Niswender, Colleen M.^1,3,4  Rodriguez, Alice L.^1,3,4  Venable, Daryl F.^1,3  Conn, P. Jeffrey^1,3,4  Lindsley, Craig W.^1,2,3,4 

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

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

[3] Vanderbilt Program Drug Discovery, Nashville, TN 37232 USA

[4] Vanderbilt Specialized Chem Ctr MLPCN, Nashville, TN 37232 USA

关键词: mGlu5;    NAM;    PAM;    Allosteric;    Metabotropic;    Glutamate;   

DOI  :  10.1016/j.bmcl.2010.11.119

来源: Elsevier

【 摘 要 】

This Letter describes a chemical lead optimization campaign directed at a weak mGlu(5) NAM discovered while developing SAR for the mGlu(5) PAM, ADX-47273. An iterative parallel synthesis effort discovered multiple, subtle molecular switches that afford potent mGlu(5) NAMs, mGlu(5) PAMs as well as mGlu(5) partial antagonists. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

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