Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Turlington, Mark^1,2,3,4  Noetzel, Meredith J.^1,2,3  Bridges, Thomas M.^1,2,3  Vinson, Paige N.^1,2,3  Steckler, Thomas⁵  Lavreysen, Hilde⁵  Mackie, Claire⁶  Bartolome-Nebreda, Jose M.⁷  Conde-Ceide, Susana⁷  Tong, Han Min⁷  Macdonald, Gregor J.⁵  Daniels, J. Scott^1,2,3  Jones, Carrie K.^1,2,3  Niswender, Colleen M.^1,2,3  Conn, P. Jeffrey^1,2,3  Lindsley, Craig W.^1,2,3,4  Stauffer, Shaun R.^1,2,3,4 

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

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

[3] Vanderbilt Specialized Chem Ctr Probe Dev MLPCN, Nashville, TN 37232 USA

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

[5] Janssen Res & Dev, Neurosci, B-2340 Beerse, Belgium

[6] Janssen Res & Dev, Discovery Sci ADME Tox, B-2340 Beerse, Belgium

[7] Janssen Res & Dev, Neurosci Med Chem, Toledo 45007, Spain

关键词: Metabotropic glutamate receptor 5 (mGlu(5));    Positive allosteric modulator (PAM);   

DOI  :  10.1016/j.bmcl.2014.04.087

来源: Elsevier

【 摘 要 】

We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of non-amide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly potent and selective PAM, 2-(phenoxymethyl)6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (11, VU0462054), bearing a simple ketone moiety, was identified (LE = 0.52, LELP = 3.2). In addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising lead properties and exploration of alternative core heterocycles, linkers, and ketone replacements, oxidative metabolism and in vivo clearance remained problematic for the series. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

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