Synthesis, structure-activity relationships, and in vivo evaluation of N3-phenylpyrazinones as novel corticotropin-releasing factor-1 (CRF1) receptor antagonists.
Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.
Hartz
Richard A
RA
Research and Development, Bristol-Myers Squibb Company, Wallingford, Connecticut 06492, USA. richard.hartz@bms.com
Ahuja
Vijay T
VT
Arvanitis
Argyrios G
AG
Rafalski
Maria
M
Yue
Eddy W
EW
Denhart
Derek J
DJ
Schmitz
William D
WD
Ditta
Jonathan L
JL
Deskus
Jeffrey A
JA
Brenner
Allison B
AB
Hobbs
Frank W
FW
Payne
Joseph
J
Lelas
Snjezana
S
Li
Yu-Wen
YW
Molski
Thaddeus F
TF
Mattson
Gail K
GK
Peng
Yong
Y
Wong
Harvey
H
Grace
James E
JE
Lentz
Kimberley A
KA
Qian-Cutrone
Jingfang
J
Zhuo
Xiaoliang
X
Shu
Yue-Zhong
YZ
Lodge
Nicholas J
NJ
Zaczek
Robert
R
Combs
Andrew P
AP
Olson
Richard E
RE
Bronson
Joanne J
JJ
Mattson
Ronald J
RJ
Macor
John E
JE
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
D011719:Pyrazines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1