Imidazo[1,2-a]pyrimidines as Functionally Selective and Orally Bioavailable GABAAα2/α3 Binding Site Agonists for the Treatment of Anxiety Disorders

• Published in: Journal of medicinal chemistry Vol. 49; no. 1; pp. 35 - 38
• Main Authors: Goodacre, Simon C, Street, Leslie J, Hallett, David J, Crawforth, James M, Kelly, Sarah, Owens, Andrew P, Blackaby, Wesley P, Lewis, Richard T, Stanley, Joanna, Smith, Alison J, Ferris, Pushpinder, Sohal, Bindi, Cook, Susan M, Pike, Andrew, Brown, Nicola, Wafford, Keith A, Marshall, George, Castro, José L, Atack, John R
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 12.01.2006
• Subjects: Biological and medical sciences; Gabaergic and benzodiazepinic system; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Agonist; Nitrile; Rat; Angular nitrogen heterocycle; Psychotropic; Anxiety disorder; Selectivity; Pyridine derivatives; Structure activity relation; Tertiary alcohol; Bicyclic compound; Dog; Fissipedia; Carnivora; Rodentia; Benzene derivatives; Oral administration; Bioavailability; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Tranquillizer; Animal; Affinity; Fluorine Organic compounds; Pharmacokinetics; Gabaergic receptor A; Subtype
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm051065l

A series of high-affinity GABAA agonists with good oral bioavailability in rat and dog and functional selectivity for the GABAAα2 and -α3 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.