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. Epub 2009 Aug 15.

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.

MeSH terms

  • 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*

Substances

  • 3-bromo-10-difluoromethyl-9H-imidazo(1,5-a)(1,2,4)triazolo(1,5-d)(1,4)benzodiazepine
  • Anticonvulsants
  • GABA-A Receptor Agonists
  • Imidazoles
  • RO 4882224
  • Receptors, GABA-A
  • Triazoles
  • Benzodiazepines