Discovery and SAR of novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5)

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Luz Martin-Martin, Maria¹  Manuel Bartolome-Nebreda, Jose¹  Conde-Ceide, Susana¹  Alonso de Diego, Sergio A.¹  Lopez, Silvia¹  Martinez-Viturro, Carlos M.¹  Han Min Tong¹  Lavreysen, Hilde²  Macdonald, Gregor J.²  Steckler, Thomas²  Mackie, Claire³  Bridges, Thomas M.^4,5,6  Daniels, J. Scott^4,5,6  Niswender, Colleen M.^4,5,6  Noetzel, Meredith J.^4,5,6  Jones, Carrie K.^4,5,6  Conn, P. Jeffrey^4,5,6  Lindsley, Craig W.^4,5,6,7  Stauffer, Shaun R.^4,5,6,7 

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

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

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

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

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

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

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

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

DOI  :  10.1016/j.bmcl.2015.01.038

来源: Elsevier

【 摘 要 】

We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu(5) PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation. (C) 2015 Elsevier Ltd. All rights reserved.

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