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.
Subject(s)
Anxiety Disorders/drug therapy , GABA-A Receptor Agonists , Imidazoles/pharmacology , Protein Subunits/agonists , Triazines/pharmacology , Administration, Oral , Animals , Ataxia/drug therapy , Binding Sites , Biological Availability , Disease Models, Animal , Dogs , Female , GABA Agonists/pharmacokinetics , GABA Agonists/pharmacology , Imidazoles/pharmacokinetics , Male , Maze Learning/drug effects , Molecular Structure , Protein Subunits/metabolism , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/metabolism , Saimiri , Structure-Activity Relationship , Triazines/pharmacokineticsABSTRACT
AIMS: This study examined the effects of two primary care interventions (a physician intervention and a clinic-based psychoeducational group) on drinking patterns, psychosocial problems and blood test results (MCV, GGT, SGOT and SGPT). DESIGN: Subjects were randomized into one of four treatment groups: physician intervention, psychoeducation, both interventions, or no intervention. Follow-up data were collected at 12 and 18 months. SETTING: Subjects were recruited from a family practice outpatient clinic managed by a public hospital. PARTICIPANTS: Included 175 Mexican-American female and male primary care patients who screened positive for alcohol abuse or dependence. These patients were not seeking help for alcohol problems. INTERVENTIONS: Included a brief physician intervention and a 6-week patient psychoeducational group. MEASUREMENTS: The Diagnostic Interview Schedule assessed subjects for alcohol abuse; the Addiction Severity Index measured alcohol-related problems, including psychosocial issues. FINDINGS: All four treatment groups demonstrated significant improvement over time, with few differences between intervention and control groups. CONCLUSIONS: Assessment can be confounded with brief interventions; future investigators should use non-assessed control groups.
