title: Discovery of the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine scaffold as a novel, potent and selective GABA(A) alpha5 inverse agonist series.
abstract: Through iterative design cycles we have discovered a number of novel new classes where the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine was deemed the most promising GABA(A) alpha5 inverse agonist class with potential for cognitive enhancement. This class combines a modest subtype binding selectivity with inverse agonism and has the most favourable molecular properties for further lead optimisation towards a central nervous system (CNS) acting medicine.
authors.affiliation: F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland.
authors.forename: Guido
authors.initials: G
authors.lastname: Achermann
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Ballard
authors.forename: Francesca
authors.initials: F
authors.lastname: Blasco
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Broutin
authors.forename: Bernd
authors.initials: B
authors.lastname: Büttelmann
authors.forename: Holger
authors.initials: H
authors.lastname: Fischer
authors.forename: Martin
authors.initials: M
authors.lastname: Graf
authors.forename: Maria-Clemencia
authors.initials: MC
authors.lastname: Hernandez
authors.forename: Peter
authors.initials: P
authors.lastname: Hilty
authors.forename: Frédéric
authors.initials: F
authors.lastname: Knoflach
authors.forename: Andreas
authors.initials: A
authors.lastname: Koblet
authors.forename: Henner
authors.initials: H
authors.lastname: Knust
authors.forename: Anke
authors.initials: A
authors.lastname: Kurt
authors.forename: James R
authors.initials: JR
authors.lastname: Martin
authors.forename: Raffaello
authors.initials: R
authors.lastname: Masciadri
authors.forename: Richard H P
authors.initials: RH
authors.lastname: Porter
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
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wichmann
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D054314:Drug Inverse Agonism; D058785:GABA-A Receptor Agonists; D006801:Humans; D018697:Nootropic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects; D011963:Receptors, GABA-A / Q000378:metabolism*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D058785:GABA-A Receptor Agonists; D018697:Nootropic Agents; D011963:Receptors, GABA-A; D014230:Triazoles; D001569:Benzodiazepines