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.
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.
Achermann
Guido
G
F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland.
Ballard
Theresa M
TM
Blasco
Francesca
F
Broutin
Pierre-Emmanuel
PE
Büttelmann
Bernd
B
Fischer
Holger
H
Graf
Martin
M
Hernandez
Maria-Clemencia
MC
Hilty
Peter
P
Knoflach
Frédéric
F
Koblet
Andreas
A
Knust
Henner
H
Kurt
Anke
A
Martin
James R
JR
Masciadri
Raffaello
R
Porter
Richard H P
RH
Stadler
Heinz
H
Thomas
Andrew W
AW
Trube
Gerhard
G
Wichmann
Jürgen
J
D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D054314:Drug Inverse Agonism; D058785:GABA-A Receptor Agonists; D006801:Humans; D018697:Nootropic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects; D011963:Receptors, GABA-A / Q000378:metabolism*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014982:Xenopus laevis
D058785:GABA-A Receptor Agonists; D018697:Nootropic Agents; D011963:Receptors, GABA-A; D014230:Triazoles; D001569:Benzodiazepines