title: Synthesis, structure-activity relationships, and in vivo evaluation of N3-phenylpyrazinones as novel corticotropin-releasing factor-1 (CRF1) receptor antagonists.
abstract: 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.
authors: Research and Development, Bristol-Myers Squibb Company, Wallingford, Connecticut 06492, USA. richard.hartz@bms.com
authors: Richard A
authors: RA
authors: Hartz
authors: Vijay T
authors: VT
authors: Ahuja
authors: Argyrios G
authors: AG
authors: Arvanitis
authors: Maria
authors: M
authors: Rafalski
authors: Eddy W
authors: EW
authors: Yue
authors: Derek J
authors: DJ
authors: Denhart
authors: William D
authors: WD
authors: Schmitz
authors: Jonathan L
authors: JL
authors: Ditta
authors: Jeffrey A
authors: JA
authors: Deskus
authors: Allison B
authors: AB
authors: Brenner
authors: Frank W
authors: FW
authors: Hobbs
authors: Joseph
authors: J
authors: Payne
authors: Snjezana
authors: S
authors: Lelas
authors: Yu-Wen
authors: YW
authors: Li
authors: Thaddeus F
authors: TF
authors: Molski
authors: Gail K
authors: GK
authors: Mattson
authors: Yong
authors: Y
authors: Peng
authors: Harvey
authors: H
authors: Wong
authors: James E
authors: JE
authors: Grace
authors: Kimberley A
authors: KA
authors: Lentz
authors: Jingfang
authors: J
authors: Qian-Cutrone
authors: Xiaoliang
authors: X
authors: Zhuo
authors: Yue-Zhong
authors: YZ
authors: Shu
authors: Nicholas J
authors: NJ
authors: Lodge
authors: Robert
authors: R
authors: Zaczek
authors: Andrew P
authors: AP
authors: Combs
authors: Richard E
authors: RE
authors: Olson
authors: Joanne J
authors: JJ
authors: Bronson
authors: Ronald J
authors: RJ
authors: Mattson
authors: John E
authors: JE
authors: Macor
mesh_terms: 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
chemical_list: D011719:Pyrazines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1