Imidazo[1,2-a]pyrimidines as functionally selective and orally bioavailable GABA(A)alpha2/alpha3 binding site agonists for the treatment of anxiety disorders

Simon C Goodacre; Leslie J Street; David J Hallett; James M Crawforth; Sarah Kelly; Andrew P Owens; Wesley P Blackaby; Richard T Lewis; Joanna Stanley; Alison J Smith; Pushpinder Ferris; Bindi Sohal; Susan M Cook; Andrew Pike; Nicola Brown; Keith A Wafford; George Marshall; José L Castro; John R Atack

doi:10.1021/jm051065l

Imidazo[1,2-a]pyrimidines as functionally selective and orally bioavailable GABA(A)alpha2/alpha3 binding site agonists for the treatment of anxiety disorders

J Med Chem. 2006 Jan 12;49(1):35-8. doi: 10.1021/jm051065l.

Affiliation

¹ Department of Medicinal Chemistry, Merck Sharp Laboratory, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, UK.

PMID: 16392789
DOI: 10.1021/jm051065l

Abstract

A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog and functional selectivity for the GABA(A)alpha2 and -alpha3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy.

MeSH terms

Administration, Oral
Animals
Anxiety Disorders / drug therapy*
Binding Sites
Biological Availability
Cell Line
Disease Models, Animal
Dogs
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
GABA-A Receptor Agonists*
Humans
Molecular Structure
Patch-Clamp Techniques
Pyrimidines / chemical synthesis
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology*
Rats
Receptors, GABA-A
Structure-Activity Relationship

Substances

GABA-A Receptor Agonists
GABRA3 protein, human
Gabra3 protein, rat
Pyrimidines
Receptors, GABA-A