Discovery of imidazo[1,2-b][1,2,4]triazines as GABA(A) alpha2/3 subtype selective agonists for the treatment of anxiety.
The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it is a nonsedating anxiolytic in both rat and squirrel monkey behavioral models.
Russell
Michael G N
MG
Carling
Robert W
RW
Street
Leslie J
LJ
Hallett
David J
DJ
Goodacre
Simon
S
Mezzogori
Elena
E
Reader
Michael
M
Cook
Susan M
SM
Bromidge
Frances A
FA
Newman
Robert
R
Smith
Alison J
AJ
Wafford
Keith A
KA
Marshall
George R
GR
Reynolds
David S
DS
Dias
Rebecca
R
Ferris
Pushpindar
P
Stanley
Jo
J
Lincoln
Rachael
R
Tye
Spencer J
SJ
Sheppard
Wayne F A
WF
Sohal
Bindi
B
Pike
Andrew
A
Dominguez
Maria
M
Atack
John R
JR
Castro
José L
JL
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D058785:GABA-A Receptor Agonists; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology; D012453:Saimiri; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; C484841:GABRA2 protein, human; C546257:GABRA3 protein, human; C546259:Gabra3 protein, rat; D007093:Imidazoles; D011963:Receptors, GABA-A; D014227:Triazines