8-(4-Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists.
This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discovery of analogue 12-3, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 4.7 +/- 2.0 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 12-3 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 12-3 has been advanced to clinical trials.
Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, Connecticut 06492, USA. paul.j.gilligan@bms.com
Paul J
PJ
Gilligan
Liqi
L
He
Todd
T
Clarke
Parcharee
P
Tivitmahaisoon
Snjezana
S
Lelas
Yu-Wen
YW
Li
Karen
K
Heman
Lawrence
L
Fitzgerald
Keith
K
Miller
Ge
G
Zhang
Anne
A
Marshall
Carol
C
Krause
John
J
McElroy
Kathyrn
K
Ward
Helen
H
Shen
Harvey
H
Wong
Scott
S
Grossman
Gregory
G
Nemeth
Robert
R
Zaczek
Stephen P
SP
Arneric
Paul
P
Hartig
David W
DW
Robertson
George
G
Trainor
D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy; D002986:Clinical Trials as Topic; D004285:Dogs; D005260:Female; D020128:Inhibitory Concentration 50; D008297:Male; D051381:Rats; D017982:Receptors, Biogenic Amine / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014227:Triazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000099052:CRF Receptor, Type 1
D014151:Anti-Anxiety Agents; D017982:Receptors, Biogenic Amine; D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; D000099052:CRF Receptor, Type 1