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.
MeSH terms
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Allosteric Regulation
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Animals
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Anti-Anxiety Agents / chemical synthesis
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Anti-Anxiety Agents / chemistry*
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Anti-Anxiety Agents / pharmacology
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Antipsychotic Agents / chemical synthesis
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Antipsychotic Agents / chemistry*
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Antipsychotic Agents / pharmacology
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CHO Cells
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Cricetulus
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Dogs
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ERG1 Potassium Channel
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Electroencephalography
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Ether-A-Go-Go Potassium Channels / physiology
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HEK293 Cells
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Humans
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Male
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Patch-Clamp Techniques
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Piperidines / chemical synthesis
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Piperidines / chemistry*
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Piperidines / pharmacology
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Pyridones / chemical synthesis
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Pyridones / chemistry*
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Pyridones / pharmacology
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Radioligand Assay
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Rats, Sprague-Dawley
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Receptors, Metabotropic Glutamate / metabolism*
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Sleep / drug effects
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Structure-Activity Relationship
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Wakefulness / drug effects
Substances
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1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone
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Anti-Anxiety Agents
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Antipsychotic Agents
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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Piperidines
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Pyridones
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Receptors, Metabotropic Glutamate
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metabotropic glutamate receptor 2