Imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepines as potent and highly selective GABAA alpha5 inverse agonists with potential for the treatment of cognitive dysfunction.
In a search for GABAA alpha5 ligands that combine high subtype binding selectivity with a marked inverse agonism imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepines were identified as a promising class. A short tandem reaction allowed rapid access to this chemical series, thereby facilitating rapid SAR generation which guided the optimization process. Two compounds (10e and 11f) were found to be active in an in vivo paradigm for cognitive improvement.
Buettelmann
Bernd
B
F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland. bernd.buettelmann@roche.com
Ballard
Theresa M
TM
Gasser
Rodolfo
R
Fischer
Holger
H
Hernandez
Maria-Clemencia
MC
Knoflach
Frédéric
F
Knust
Henner
H
Stadler
Heinz
H
Thomas
Andrew W
AW
Trube
Gerhard
G
D000759:Adjuvants, Anesthesia / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D003072:Cognition Disorders / Q000188:drug therapy*; D054314:Drug Inverse Agonism; D058785:GABA-A Receptor Agonists; D006801:Humans; D008570:Memory, Short-Term / Q000187:drug effects; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000759:Adjuvants, Anesthesia; D000927:Anticonvulsants; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D014230:Triazoles; D001569:Benzodiazepines; D012601:Scopolamine