The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABAA alpha5 inverse agonists for the treatment of cognitive dysfunction.
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.
Knust
Henner
H
F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland. henner.knust@roche.com
Achermann
Guido
G
Ballard
Theresa
T
Buettelmann
Bernd
B
Gasser
Rodolfo
R
Fischer
Holger
H
Hernandez
Maria-Clemencia
MC
Knoflach
Frédéric
F
Koblet
Andreas
A
Stadler
Heinz
H
Thomas
Andrew W
AW
Trube
Gerhard
G
Waldmeier
Pius
P
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D002460:Cell Line; D003072:Cognition Disorders / Q000188:drug therapy*; D004195:Disease Models, Animal; D055808:Drug Discovery; D054314:Drug Inverse Agonism; D058785:GABA-A Receptor Agonists; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D011485:Protein Binding; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*
C542509:3-bromo-10-difluoromethyl-9H-imidazo(1,5-a)(1,2,4)triazolo(1,5-d)(1,4)benzodiazepine; D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; D007093:Imidazoles; C546015:RO 4882224; D011963:Receptors, GABA-A; D014230:Triazoles; D001569:Benzodiazepines