The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABA A α5 inverse agonists for the treatment of cognitive dysfunction

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 20; pp. 5940 - 5944
• 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: Elsevier Ltd 2009
• Subjects: Clinical candidate; GABA A receptor subtypes; Lead optimisation; Neuroscience; Neuroscience; GABA A receptor subtypes; Clinical candidate; Lead optimisation
• ISSN: 0960-894X; 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 GABA A α5 inverse agonists. The unique pharmacological profiles and optimal pharmacokinetic profiles resulted in in vivo activity in selected cognition models. 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 GABA A α5 inverse agonists. The unique pharmacological profiles and optimal pharmacokinetic profiles resulted in in vivo activity in selected cognition models.