Synthesis and structure-activity relationships of 8-(pyrid-3-yl)pyrazolo[1,5-a]-1,3,5-triazines: potent, orally bioavailable corticotropin releasing factor receptor-1 (CRF1) antagonists.
This report describes the syntheses and structure-activity relationships of 8-(substituted pyridyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. These CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research resulted in the discovery of compound 13-15, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 6.1 +/- 0.6 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 13-15 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 13-15 has been advanced to clinical trials.
Bristol-Myers Squibb Co., 311 Pennington-Rocky Hill Road, Hopewell, New Jersey 08540, USA. paul.j.gilligan@bms.com
Paul J
PJ
Gilligan
Todd
T
Clarke
Liqi
L
He
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 F
JF
McElroy
Kathyrn
K
Ward
Kim
K
Zeller
Harvey
H
Wong
Steven
S
Bai
Joanne
J
Saye
Scott
S
Grossman
Robert
R
Zaczek
Stephen P
SP
Arneric
Paul
P
Hartig
David
D
Robertson
George
G
Trainor
D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001682:Biological Availability; D002986:Clinical Trials as Topic; D004285:Dogs; D020128:Inhibitory Concentration 50; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship; D014227:Triazines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014867:Water / Q000737:chemistry; D000099052:CRF Receptor, Type 1
D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; D014867:Water; D000099052:CRF Receptor, Type 1