7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid(A) (GABA(A)) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models.
There is increasing evidence that compounds with selectivity for gamma-aminobutyric acid(A) (GABA(A)) alpha2- and/or alpha3-subtypes may retain the desirable anxiolytic activity of nonselective benzodiazepines but possess an improved side effect profile. Herein we describe a novel series of GABA(A) alpha2/alpha3 subtype-selective agonists leading to the identification of the development candidate 17, a nonsedating anxiolytic in preclinical animal assays.
Carling
Robert W
RW
Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. robert_carling@merck.com
Madin
Andrew
A
Guiblin
Alec
A
Russell
Michael G N
MG
Moore
Kevin W
KW
Mitchinson
Andrew
A
Sohal
Bindi
B
Pike
Andrew
A
Cook
Susan M
SM
Ragan
Ian C
IC
McKernan
Ruth M
RM
Quirk
Kathleen
K
Ferris
Pushpinder
P
Marshall
George
G
Thompson
Sally Ann
SA
Wafford
Keith A
KA
Dawson
Gerard R
GR
Atack
John R
JR
Harrison
Timothy
T
Castro
José L
JL
Street
Leslie J
LJ
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D004285:Dogs; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011323:Primates; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology; D011994:Recombinant Proteins / Q000819:agonists; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014981:Xenopus
C507018:7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo(4,3-b)pyridazine; D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; C546240:GABRA1 protein, human; C484841:GABRA2 protein, human; C546257:GABRA3 protein, human; C546241:Gabra1 protein, mouse; C546258:Gabra3 protein, mouse; D006993:Hypnotics and Sedatives; D011724:Pyridazines; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D014230:Triazoles