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Bioorg Med Chem Lett. 2015 Mar 15;25(6):1310-7. doi: 10.1016/j.bmcl.2015.01.038. Epub 2015 Jan 28.

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

Author information

1
Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain. Electronic address: mlmartin@its.jnj.com.
2
Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain.
3
Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
4
Discovery Sciences ADME/Tox, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
5
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
6
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.

Abstract

We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) 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 mGlu5 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.

KEYWORDS:

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

PMID:
25683622
PMCID:
PMC4399811
DOI:
10.1016/j.bmcl.2015.01.038
[Indexed for MEDLINE]
Free PMC Article

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