Abstract
1,4-Benzodiazepines are used in the treatment of anxiety disorders but have limited long-term use due to adverse effects. HZ-166 (2) has been shown to have anxiolytic-like effects with reduced sedative/ataxic liabilities. A 1,3-oxazole KRM-II-81 (9) was discovered from a series of six bioisosteres with significantly improved pharmacokinetic and pharmacodynamic properties as compared to 2. Oxazole 9 was further characterized and exhibited improved anxiolytic-like effects in a mouse marble burying assay and a rat Vogel conflict test.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Anti-Anxiety Agents / chemistry
-
Anti-Anxiety Agents / metabolism
-
Anti-Anxiety Agents / pharmacology*
-
Anxiety / drug therapy
-
Benzodiazepines / chemistry
-
Benzodiazepines / metabolism
-
Benzodiazepines / pharmacology*
-
Dose-Response Relationship, Drug
-
Epilepsy / drug therapy
-
GABA-A Receptor Antagonists / chemistry
-
GABA-A Receptor Antagonists / metabolism
-
GABA-A Receptor Antagonists / pharmacology*
-
HEK293 Cells
-
Humans
-
Imidazoles / chemistry
-
Imidazoles / metabolism
-
Imidazoles / pharmacology*
-
Ligands
-
Male
-
Mice
-
Mice, Inbred Strains
-
Molecular Structure
-
Oxazoles / chemistry
-
Oxazoles / metabolism
-
Oxazoles / pharmacology*
-
Pain / drug therapy
-
Rats
-
Rats, Sprague-Dawley
-
Receptors, GABA-A / metabolism*
-
Structure-Activity Relationship
Substances
-
8-ethynyl-6-(2'-pyridine)-4H-2,5,10b-triazabenzo(e)azulene-3-carboxylic acid ethyl ester
-
Anti-Anxiety Agents
-
GABA-A Receptor Antagonists
-
Imidazoles
-
KRM-II-81
-
Ligands
-
Oxazoles
-
Receptors, GABA-A
-
Benzodiazepines