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

  • Bioorg Med Chem Lett. 2009 Oct 15;19(20):5940-4. doi: 10.1016/j.bmcl.2009.08.053.
Henner Knust  1 ,  Guido Achermann ,  Theresa Ballard ,  Bernd Buettelmann ,  Rodolfo Gasser ,  Holger Fischer ,  Maria-Clemencia Hernandez ,  Frédéric Knoflach ,  Andreas Koblet ,  Heinz Stadler ,  Andrew W Thomas ,  Gerhard Trube ,  Pius Waldmeier
Affiliations
  • 1. F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland. [email protected]
PMID: 19762240 DOI: 10.1016/j.bmcl.2009.08.053
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.

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