title: Imidazo[1,2-a]pyrimidines as functionally selective and orally bioavailable GABA(A)alpha2/alpha3 binding site agonists for the treatment of anxiety disorders.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Sharp Laboratory, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, UK.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Goodacre
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Street
authors.forename: David J
authors.initials: DJ
authors.lastname: Hallett
authors.forename: James M
authors.initials: JM
authors.lastname: Crawforth
authors.forename: Sarah
authors.initials: S
authors.lastname: Kelly
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Owens
authors.forename: Wesley P
authors.initials: WP
authors.lastname: Blackaby
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lewis
authors.forename: Joanna
authors.initials: J
authors.lastname: Stanley
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Pushpinder
authors.initials: P
authors.lastname: Ferris
authors.forename: Bindi
authors.initials: B
authors.lastname: Sohal
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cook
authors.forename: Andrew
authors.initials: A
authors.lastname: Pike
authors.forename: Nicola
authors.initials: N
authors.lastname: Brown
authors.forename: Keith A
authors.initials: KA
authors.lastname: Wafford
authors.forename: George
authors.initials: G
authors.lastname: Marshall
authors.forename: José L
authors.initials: JL
authors.lastname: Castro
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
mesh_terms: 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
chemical_list: D058785:GABA-A Receptor Agonists; C546257:GABRA3 protein, human; C546259:Gabra3 protein, rat; D011743:Pyrimidines; D011963:Receptors, GABA-A