Optimization of an ether series of mGlu5 positive allosteric modulators: Molecular determinants of MPEP-site interaction crossover

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Manka, Jason T.^1,2,3  Vinson, Paige N.^1,2  Gregory, Karen J.^1,2,9,10  Zhou, Ya^1,2,3  Williams, Richard^1,2,3  Gogi, Kiran^1,2  Days, Emily^1,5  Jadhav, Satya^1,2  Herman, Elizabeth J.^1,2  Lavreysen, Hilde⁶  Mackie, Claire⁷  Bartolome, Jose M.⁸  Macdonald, Gregor J.⁶  Steckler, Thomas⁶  Daniels, J. Scott^1,2,3  Weaver, C. David^1,5  Niswender, Colleen M.^1,2,3  Jones, Carrie K.^1,2,3,11  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] Vanderbilt Univ, Vanderbilt Inst Chem Biol, Nashville, TN 37232 USA

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

[7] Janssen Res & Dev, CREATe ADME Tox, B-2340 Beerse, Belgium

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

[9] Monash Univ, MIPS, Parkville, Vic, Australia

[10] Monash Univ, Dept Pharmacol, Parkville, Vic, Australia

[11] US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN 37212 USA

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

DOI  :  10.1016/j.bmcl.2012.08.043

来源: Elsevier

【 摘 要 】

We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site. (c) 2012 Elsevier Ltd. All rights reserved.

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