The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABAA alpha5 inverse agonists for the treatment of cognitive dysfunction

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 20; p. 5940
• Main Authors: Knust, Henner, Achermann, Guido, Ballard, Theresa, Buettelmann, Bernd, Gasser, Rodolfo, Fischer, Holger, Hernandez, Maria-Clemencia, Knoflach, Frédéric, Koblet, Andreas, Stadler, Heinz, Thomas, Andrew W, Trube, Gerhard, Waldmeier, Pius
• Format: Journal Article
• Language: English
• Published: England 15.10.2009
• Subjects: Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - pharmacokinetics; Benzodiazepines - chemical synthesis; Benzodiazepines - chemistry; Benzodiazepines - pharmacokinetics; Cell Line; Cognition Disorders - drug therapy; Disease Models, Animal; Drug Discovery; Drug Inverse Agonism; GABA-A Receptor Agonists; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacokinetics; Mice; Protein Binding; Rats; Receptors, GABA-A - metabolism; Seizures - chemically induced; Seizures - drug therapy; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacokinetics
• ISSN: 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2009.08.053

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.