Discovery of 1-Butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1 H )-pyridone (JNJ-40411813): A Novel Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor
Citations Over TimeTop 10% of 2014 papers
Abstract
We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this article, we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine-substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. The fine tuning of metabolism and hERG followed by differentiation of advanced leads that were identified on the basis of PK profiles and in vivo potency converged on lead compound 36 (JNJ-40411813). Full in vitro and in vivo profiles indicate that 36 displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Compound 36 has been investigated in the clinic for schizophrenia and anxious depression disorders.
Related Papers
- → Mechanism of β 2 AR regulation by an intracellular positive allosteric modulator(2019)131 cited
- → Identification and Characterization of the First Selective Y4 Receptor Positive Allosteric Modulator(2017)12 cited
- → Determining Allosteric Modulator Mechanism of Action: Integration of Radioligand Binding and Functional Assay Data(2011)17 cited
- → 6-Phenylpyrimidin-4-ones as Positive Allosteric Modulators at the M1 mAChR: The Determinants of Allosteric Activity(2018)11 cited
- → G protein-coupled receptor allosteric modulators(2019)