Imidazo[1,2-a]pyrimidines as functionally selective and orally bioavailable GABA(A)alpha2/alpha3 binding site agonists for the treatment of anxiety disorders.
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.
Goodacre
Simon C
SC
Department of Medicinal Chemistry, Merck Sharp Laboratory, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, UK.
Street
Leslie J
LJ
Hallett
David J
DJ
Crawforth
James M
JM
Kelly
Sarah
S
Owens
Andrew P
AP
Blackaby
Wesley P
WP
Lewis
Richard T
RT
Stanley
Joanna
J
Smith
Alison J
AJ
Ferris
Pushpinder
P
Sohal
Bindi
B
Cook
Susan M
SM
Pike
Andrew
A
Brown
Nicola
N
Wafford
Keith A
KA
Marshall
George
G
Castro
José L
JL
Atack
John R
JR
D000284:Administration, Oral; D000818:Animals; D001008:Anxiety Disorders / Q000188:drug therapy*; D001665:Binding Sites; D001682:Biological Availability; D002460:Cell Line; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D058785:GABA-A Receptor Agonists; D006801:Humans; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A; D013329:Structure-Activity Relationship
D058785:GABA-A Receptor Agonists; C546257:GABRA3 protein, human; C546259:Gabra3 protein, rat; D011743:Pyrimidines; D011963:Receptors, GABA-A