ABSTRACT
Imidazo[1,2-a]pyridines were identified via their shape and electrostatic similarity as novel positive allosteric modulators of the metabotropic glutamate 2 receptor. The subsequent synthesis and SAR are described. Potent, selective and metabolically stable compounds were found representing a promising avenue for current further studies.
Subject(s)
Imidazoles/chemistry , Pyridines/chemistry , Pyridones/chemistry , Receptors, Metabotropic Glutamate/chemistry , Allosteric Regulation , Animals , Humans , Microsomes, Liver/metabolism , Pyridines/chemical synthesis , Pyridines/pharmacology , Rats , Receptors, Metabotropic Glutamate/metabolism , Static Electricity , Structure-Activity RelationshipABSTRACT
Starting from two weak mGlu2 receptor positive allosteric modulator (PAM) HTS hits (4 and 5), a molecular hybridization strategy resulted in the identification of a novel spiro-oxindole piperidine series with improved activity and metabolic stability. Scaffold hopping around the spiro-oxindole core identified the 3-(azetidin-3-yl)-1H-benzimidazol-2-one as bioisoster. Medicinal chemistry optimization of these two novel chemotypes resulted in the identification of potent, selective, orally bioavailable, and brain penetrant mGluR2 PAMs.
ABSTRACT
Positive allosteric modulators of the metabotropic glutamate 2 receptor have generated great interest in the past decade. There is mounting evidence of their potential as therapeutic agents in the treatment of multiple central nervous system disorders. We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs. However, finding compounds with the optimal combination of in vitro potency and good druglike properties has remained elusive, in part because of the hydrophobic nature of the allosteric binding site. Herein, we report on the lead optimization process to overcome the poor solubility inherent to the advanced lead 6. Initial prototypes already showed significant improvements in solubility while retaining good functional activity but displayed new liabilities associated with metabolism and hERG inhibition. Subsequent subtle modifications efficiently addressed those issues leading to the identification of compound 27 (JNJ-46356479). This new lead represents a more balanced profile that offers a significant improvement on the druglike attributes compared to previously reported leads.
Subject(s)
Pyridines/chemistry , Pyridines/pharmacology , Receptors, Metabotropic Glutamate/agonists , Triazoles/chemistry , Triazoles/pharmacology , Administration, Oral , Allosteric Regulation/drug effects , Animals , CHO Cells , Caco-2 Cells , Cricetulus , Dogs , Humans , Male , Models, Molecular , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Rats , Receptors, Metabotropic Glutamate/metabolism , Triazoles/administration & dosage , Triazoles/pharmacokineticsABSTRACT
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.
Subject(s)
Anti-Anxiety Agents/chemistry , Antipsychotic Agents/chemistry , Piperidines/chemistry , Pyridones/chemistry , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/pharmacology , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacology , CHO Cells , Cricetulus , Dogs , ERG1 Potassium Channel , Electroencephalography , Ether-A-Go-Go Potassium Channels/physiology , HEK293 Cells , Humans , Male , Patch-Clamp Techniques , Piperidines/chemical synthesis , Piperidines/pharmacology , Pyridones/chemical synthesis , Pyridones/pharmacology , Radioligand Assay , Rats, Sprague-Dawley , Sleep/drug effects , Structure-Activity Relationship , Wakefulness/drug effectsABSTRACT
The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep-wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.
Subject(s)
Nitriles/chemical synthesis , Pyridones/chemical synthesis , Receptors, Metabotropic Glutamate/agonists , Allosteric Regulation , Animals , Brain/metabolism , Drug Synergism , ERG1 Potassium Channel , Electroencephalography , Ether-A-Go-Go Potassium Channels/physiology , HEK293 Cells , Humans , Isomerism , Mice , Nitriles/pharmacokinetics , Nitriles/pharmacology , Patch-Clamp Techniques , Pyridones/pharmacokinetics , Pyridones/pharmacology , Rats , Receptors, Metabotropic Glutamate/metabolism , Sleep, REM/drug effects , Structure-Activity Relationship , WakefulnessABSTRACT
Advanced leads of an imidazopyridine series of positive allosteric modulators of the metabotropic glutamate 2 (mGlu2) receptor are reported. The optimization of in vitro ADMET and in vivo pharmacokinetic properties led to the identification of 27o. With good potency and selectivity for the mGlu2 receptor, 27o affected sleep-wake architecture in rats after oral treatment, which we have previously shown to be indicative of mGlu2 receptor-mediated central activity.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Imidazoles/chemical synthesis , Indoles/chemical synthesis , Pyridines/chemical synthesis , Receptors, Metabotropic Glutamate/metabolism , Administration, Oral , Allosteric Regulation , Animals , Biological Availability , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line , Cricetinae , Cricetulus , Cytochrome P-450 Enzyme Inhibitors , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Indoles/pharmacokinetics , Indoles/pharmacology , Ion Channels/antagonists & inhibitors , Male , Mice , Microsomes, Liver/metabolism , Pyridines/pharmacokinetics , Pyridines/pharmacology , Radioligand Assay , Rats , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Sleep/drug effects , Structure-Activity Relationship , Wakefulness/drug effectsABSTRACT
Advanced leads from a series of 1,2,4-triazolo[4,3-a]pyridines with mGlu2 receptor PAM activity are reported. By modification of the analogous imidazo[1,2-a]pyridine series, the newly reported leads have improved potency, in vitro ADMET, and hERG as well as good in vivo PK profile. The optimization of the series focused on improving metabolic stability while controlling lipophilicity by introducing small modifications to the scaffold substituents. Analysis of this series combined with our previously reported mGlu2 receptor PAMs showed how lipophilic ligand efficiency was improved during the course of the program. Among the best compounds, example 20 (JNJ-42153605) showed a central in vivo efficacy by inhibition of REM sleep state at a dose of 3 mg/kg po in the rat sleep-wake EEG paradigm, a phenomenon shown earlier to be mGlu2 mediated. In mice, compound 20 reversed PCP-induced hyperlocomotion with an ED50 of 5.4 mg/kg sc, indicative of antipsychotic activity.
Subject(s)
Antipsychotic Agents/chemical synthesis , Pyridines/chemical synthesis , Receptors, Metabotropic Glutamate/metabolism , Triazines/chemical synthesis , Allosteric Regulation , Animals , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/pharmacology , Blood-Brain Barrier/metabolism , Cell Line , ERG1 Potassium Channel , Electroencephalography , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Hyperkinesis/drug therapy , Male , Mice , Microsomes, Liver/metabolism , Patch-Clamp Techniques , Polysomnography , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Sleep/drug effects , Structure-Activity Relationship , Triazines/pharmacokinetics , Triazines/pharmacology , Wakefulness/drug effectsABSTRACT
A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.