title: Imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepines as potent and highly selective GABAA alpha5 inverse agonists with potential for the treatment of cognitive dysfunction.
abstract: In a search for GABAA alpha5 ligands that combine high subtype binding selectivity with a marked inverse agonism imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepines were identified as a promising class. A short tandem reaction allowed rapid access to this chemical series, thereby facilitating rapid SAR generation which guided the optimization process. Two compounds (10e and 11f) were found to be active in an in vivo paradigm for cognitive improvement.
authors.affiliation: F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland. bernd.buettelmann@roche.com
authors.forename: Bernd
authors.initials: B
authors.lastname: Buettelmann
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Ballard
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Gasser
authors.forename: Holger
authors.initials: H
authors.lastname: Fischer
authors.forename: Maria-Clemencia
authors.initials: MC
authors.lastname: Hernandez
authors.forename: Frédéric
authors.initials: F
authors.lastname: Knoflach
authors.forename: Henner
authors.initials: H
authors.lastname: Knust
authors.forename: Heinz
authors.initials: H
authors.lastname: Stadler
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Thomas
authors.forename: Gerhard
authors.initials: G
authors.lastname: Trube
mesh_terms: D000759:Adjuvants, Anesthesia / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D003072:Cognition Disorders / Q000188:drug therapy*; D054314:Drug Inverse Agonism; D058785:GABA-A Receptor Agonists; D006801:Humans; D008570:Memory, Short-Term / Q000187:drug effects; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000759:Adjuvants, Anesthesia; D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D014230:Triazoles; D001569:Benzodiazepines; D012601:Scopolamine