ABSTRACT
A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40-41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10⯵mol/kg compared to control.
Subject(s)
Benzamides/pharmacology , Bridged Bicyclo Compounds/pharmacology , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Administration, Oral , Animals , Benzamides/administration & dosage , Benzamides/chemistry , Bridged Bicyclo Compounds/administration & dosage , Bridged Bicyclo Compounds/chemistry , Dose-Response Relationship, Drug , Humans , Injections, Intravenous , Locomotion/drug effects , Male , Mice , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of 4-piperidin-4-ylidenemethyl-benzamide δ-opioid receptor agonists is described with an emphasis on balancing the potency, subtype selectivity and in vitro ADME and safety properties. The three sites impacting SAR are substitutions on the aryl group (R(1)), the piperidine nitrogen (R(2)), and the amide (R(3)). Each region contributes to the balance of properties for δ opioid activity and a desirable CNS profile, and two clinical candidates (20 and 24) were advanced.
Subject(s)
Benzamides/pharmacology , Central Nervous System/drug effects , Piperidines/pharmacology , Receptors, Opioid, delta/agonists , Benzamides/chemistry , Central Nervous System/metabolism , Dose-Response Relationship, Drug , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , HEK293 Cells , Humans , Molecular Structure , Piperidines/chemistry , Receptors, Opioid, delta/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel series of piperazine derivatives exhibits sub-nanomolar binding and enhanced subtype selectivity as δ-opioid agonists. The synthesis and SAR are described as well as the application of computational models to improve in vitro ADME and safety properties suitable for CNS indications, specifically microsomal clearance, permeability, and hERG channel inhibition.
