Discovery of the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine scaffold as a novel, potent and selective GABA(A) alpha5 inverse agonist series

Guido Achermann; Theresa M Ballard; Francesca Blasco; Pierre-Emmanuel Broutin; Bernd Büttelmann; Holger Fischer; Martin Graf; Maria-Clemencia Hernandez; Peter Hilty; Frédéric Knoflach; Andreas Koblet; Henner Knust; Anke Kurt; James R Martin; Raffaello Masciadri; Richard H P Porter; Heinz Stadler; Andrew W Thomas; Gerhard Trube; Jürgen Wichmann

doi:10.1016/j.bmcl.2009.07.153

Discovery of the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine scaffold as a novel, potent and selective GABA(A) alpha5 inverse agonist series

Bioorg Med Chem Lett. 2009 Oct 1;19(19):5746-52. doi: 10.1016/j.bmcl.2009.07.153. Epub 2009 Aug 4.

Affiliation

¹ F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland.

PMID: 19726184
DOI: 10.1016/j.bmcl.2009.07.153

Abstract

Through iterative design cycles we have discovered a number of novel new classes where the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine was deemed the most promising GABA(A) alpha5 inverse agonist class with potential for cognitive enhancement. This class combines a modest subtype binding selectivity with inverse agonism and has the most favourable molecular properties for further lead optimisation towards a central nervous system (CNS) acting medicine.

MeSH terms

Animals
Benzodiazepines / chemical synthesis
Benzodiazepines / chemistry*
Benzodiazepines / pharmacology
Drug Discovery
Drug Inverse Agonism
GABA-A Receptor Agonists
Humans
Nootropic Agents / chemical synthesis
Nootropic Agents / chemistry*
Nootropic Agents / pharmacology
Oocytes / drug effects
Receptors, GABA-A / metabolism*
Triazoles / chemical synthesis
Triazoles / chemistry*
Triazoles / pharmacology
Xenopus laevis

Substances

GABA-A Receptor Agonists
Nootropic Agents
Receptors, GABA-A
Triazoles
Benzodiazepines