title: The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABAA alpha5 inverse agonists for the treatment of cognitive dysfunction.
abstract: Lead optimisation of the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine class led to the identification of two clinical leads [RO4882224 (11) and RO4938581 (44)] functioning as novel potent and selective GABAA alpha5 inverse agonists. The unique pharmacological profiles and optimal pharmacokinetic profiles resulted in in vivo activity in selected cognition models.
authors.affiliation: F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland. henner.knust@roche.com
authors.forename: Henner
authors.initials: H
authors.lastname: Knust
authors.forename: Guido
authors.initials: G
authors.lastname: Achermann
authors.forename: Theresa
authors.initials: T
authors.lastname: Ballard
authors.forename: Bernd
authors.initials: B
authors.lastname: Buettelmann
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: Andreas
authors.initials: A
authors.lastname: Koblet
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: Pius
authors.initials: P
authors.lastname: Waldmeier
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D002460:Cell Line; D003072:Cognition Disorders / Q000188:drug therapy*; D004195:Disease Models, Animal; D055808:Drug Discovery; D054314:Drug Inverse Agonism; D058785:GABA-A Receptor Agonists; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D011485:Protein Binding; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: C542509:3-bromo-10-difluoromethyl-9H-imidazo(1,5-a)(1,2,4)triazolo(1,5-d)(1,4)benzodiazepine; D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; D007093:Imidazoles; C546015:RO 4882224; D011963:Receptors, GABA-A; D014230:Triazoles; D001569:Benzodiazepines