ABSTRACT
Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.
Subject(s)
Drug Discovery , Epilepsy/drug therapy , Ion Channel Gating/drug effects , KCNQ2 Potassium Channel/metabolism , Piperidines/pharmacology , Pyrimidines/pharmacology , Animals , Cell Line , Dose-Response Relationship, Drug , Electroshock , Humans , KCNQ2 Potassium Channel/agonists , Microsomes/drug effects , Molecular Structure , Piperidines/administration & dosage , Piperidines/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Compounds with combined norepinephrine reuptake inhibitor (NRI) and serotonin 1A (5-HT(1A)) partial agonist pharmacology may offer a new therapeutic approach for treating symptoms of neuropsychiatric disorders including ADHD, depression, and anxiety. Herein we describe the design and optimization of novel chemical matter that exhibits favorable dual NRI and 5-HT(1A) partial agonist activity. Lead compounds in this series were found to be devoid of activity at the dopamine transporter and were shown to be brain penetrant with high receptor occupancy.
Subject(s)
Adrenergic Uptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/pharmacology , Norepinephrine/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Agonists/chemistry , Serotonin 5-HT1 Receptor Agonists/pharmacology , Adrenergic Uptake Inhibitors/pharmacokinetics , Animals , Anxiety/drug therapy , Attention Deficit Disorder with Hyperactivity/drug therapy , Azetidines/chemistry , Azetidines/pharmacokinetics , Azetidines/pharmacology , Brain/metabolism , Depressive Disorder/drug therapy , Dogs , Humans , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Serotonin 5-HT1 Receptor Agonists/pharmacokineticsABSTRACT
Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT(1A) partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT(1A) partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.
