Substituted tetraazaacenaphthylenes as potent CRF1 receptor antagonists for the treatment of depression and anxiety.
Two isomers of the hexahydro-tetraazaacenaphthylene templates (1 and 2) are presented as novel, potent, and selective corticotropin releasing factor-1 (CRF1) receptor antagonists. In this paper, we report the affinity and SAR of a series of compounds, as well as pharmacokinetic characterization of a chosen set. The anxiolitic activity of a selected example (2ba) in the rat pup vocalization model is also presented.
St-Denis
Y
Y
Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Center, Via A. Fleming 4, 37135 Verona, Italy. yves.a.stdenis@gsk.com
Di Fabio
R
R
Bernasconi
G
G
Castiglioni
E
E
Contini
S
S
Donati
D
D
Fazzolari
E
E
Gentile
G
G
Ghirlanda
D
D
Marchionni
C
C
Messina
F
F
Micheli
F
F
Pavone
F
F
Pasquarello
A
A
Sabbatini
F M
FM
Zampori
M G
MG
Arban
R
R
Vitulli
G
G
D000073:Acenaphthenes / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
D000073:Acenaphthenes; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1