ABSTRACT
Amalgamation of the structure-activity relationship of two series of GlyT1 inhibitors developed at Merck led to the discovery of a clinical candidate, compound 16 (DCCCyB), which demonstrated excellent in vivo occupancy of GlyT1 transporters in rhesus monkey as determined by displacement of a PET tracer ligand.
ABSTRACT
A series of heterocyclic sulfonamides have been developed which are potent and selective inhibitors of hGlyT1. SAR studies to optimise the in vitro and in vivo properties are described. Optimisation of the central scaffold resulted in cyclohexane sulfones 28 and 29, which have good PK properties and show promise for further development.
Subject(s)
Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Sulfonamides/administration & dosage , Sulfonamides/chemistry , Administration, Oral , Animals , Biological Availability , Glycine Plasma Membrane Transport Proteins/metabolism , Humans , Male , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Rats , Rats, Sprague-Dawley , Sulfonamides/metabolism , Triazoles/administration & dosage , Triazoles/chemical synthesisABSTRACT
The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.
Subject(s)
Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , GABA Agonists/pharmacology , GABA-A Receptor Agonists , Pyridazines/pharmacology , Animals , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/chemical synthesis , Binding Sites , GABA Agonists/administration & dosage , GABA Agonists/chemical synthesis , Humans , Ligands , Molecular Structure , Pyridazines/administration & dosage , Pyridazines/chemical synthesis , Rats , Recombinant Proteins/agonists , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Imidazo[1,2-a]pyrimidines and imidazo[1,2-b][1,2,4]triazines are ligands for the benzodiazepine binding site of GABA(A) receptors that are functionally selective for the alpha2/alpha3 subtypes over the alpha1 subtype. SAR studies to optimise this functional selectivity, pharmacokinetic and behavioural data are described.
