Synthesis and Characterization of a Novel γ-Aminobutyric Acid Type A (GABAA) Receptor Ligand That Combines Outstanding Metabolic Stability, Pharmacokinetics, and Anxiolytic Efficacy. J Med Chem 2016 Dec 08;59(23):10800-10806
Date
12/10/2016Pubmed ID
27933953Pubmed Central ID
PMC5215686DOI
10.1021/acs.jmedchem.6b01332Scopus ID
2-s2.0-85003442743 (requires institutional sign-in at Scopus site) 40 CitationsAbstract
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.
Author List
Poe MM, Methuku KR, Li G, Verma AR, Teske KA, Stafford DC, Arnold LA, Cramer JW, Jones TM, Cerne R, Krambis MJ, Witkin JM, Jambrina E, Rehman S, Ernst M, Cook JM, Schkeryantz JMAuthors
Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - MilwaukeeJames M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee
MESH terms used to index this publication - Major topics in bold
AnimalsAnti-Anxiety Agents
Anxiety
Benzodiazepines
Dose-Response Relationship, Drug
Epilepsy
GABA-A Receptor Antagonists
HEK293 Cells
Humans
Imidazoles
Ligands
Male
Mice
Mice, Inbred Strains
Molecular Structure
Oxazoles
Pain
Rats
Rats, Sprague-Dawley
Receptors, GABA-A
Structure-Activity Relationship
