Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M5 PAM

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

Bridges, Thomas M.^1,4  Kennedy, J. Phillip^2,4  Cho, Hyekyung P.^1,3,4  Breininger, Micah L.^1,4  Gentry, Patrick R.^1,3,4  Hopkins, Corey R.^1,3,4  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: M5;    Muscarinic receptor;    Allosteric;    Positive allosteric modualtor;    PAM;   

DOI  :  10.1016/j.bmcl.2009.11.089

来源: Elsevier

【 摘 要 】

This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M-5-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G(q) mAChR M-1, M-3, M-5 PAM. An iterative library synthesis approach delivered the first selective M-5 PAM (no activity at M-1-M-4 @ 30 mu M), and an important tool compound to study the role of M-5 in the CNS. (C) 2009 Elsevier Ltd. All rights reserved.

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