ABSTRACT
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.
Subject(s)
Central Nervous System/drug effects , Piperazines/pharmacology , Receptors, Opioid, delta/agonists , Animals , Central Nervous System/metabolism , Computer Simulation , Dogs , Dose-Response Relationship, Drug , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Receptors, Opioid, delta/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) is regarded as a potential novel treatment for schizophrenic patients. Herein we report the synthesis and SAR of 4-aryl piperazine and piperidine amides as potent mGluR5 positive allosteric modulators (PAMs). Several analogs have excellent activity and desired drug-like properties. Compound 2b was further characterized as a PAM using several in vitro experiments, and produced robust activity in several preclinical animal models.
