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

María Luz Martín-Martín; José Manuel Bartolomé-Nebreda; Susana Conde-Ceide; Sergio A Alonso de Diego; Silvia López; Carlos M Martínez-Viturro; Han Min Tong; Hilde Lavreysen; Gregor J Macdonald; Thomas Steckler; Claire Mackie; Thomas M Bridges; J Scott Daniels; Colleen M Niswender; Meredith J Noetzel; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley; Shaun R Stauffer

doi:10.1016/j.bmcl.2015.01.038

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

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

Authors

María Luz Martín-Martín¹, José Manuel Bartolomé-Nebreda², Susana Conde-Ceide², Sergio A Alonso de Diego², Silvia López², Carlos M Martínez-Viturro², Han Min Tong², Hilde Lavreysen³, Gregor J Macdonald³, Thomas Steckler³, Claire Mackie⁴, Thomas M Bridges⁵, J Scott Daniels⁵, Colleen M Niswender⁵, Meredith J Noetzel⁵, Carrie K Jones⁵, P Jeffrey Conn⁵, Craig W Lindsley⁶, Shaun R Stauffer⁶

Affiliations

¹ Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain. Electronic address: [email protected].
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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Allosteric Regulation
Animals
Antipsychotic Agents / chemical synthesis
Antipsychotic Agents / chemistry*
Antipsychotic Agents / pharmacokinetics
Brain / metabolism
Drug Evaluation, Preclinical
Half-Life
Heterocyclic Compounds, 2-Ring / chemical synthesis
Heterocyclic Compounds, 2-Ring / chemistry*
Heterocyclic Compounds, 2-Ring / pharmacokinetics
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry*
Imidazoles / pharmacokinetics
Locomotion / drug effects
Microsomes, Liver / metabolism
Protein Binding
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry*
Pyrimidinones / pharmacokinetics
Rats
Receptor, Metabotropic Glutamate 5 / chemistry*
Receptor, Metabotropic Glutamate 5 / metabolism
Structure-Activity Relationship

Substances

Antipsychotic Agents
Heterocyclic Compounds, 2-Ring
Imidazoles
Pyrimidinones
Receptor, Metabotropic Glutamate 5
imidazole

Abstract

Publication types

MeSH terms

Substances

Grants and funding