Synthesis, structure-activity relationships, and in vivo properties of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones as corticotropin-releasing factor-1 receptor antagonists

被引：13

作者：

Dzierba, CD ^{[1
]}

Takvorian, AG ^{[1
]}

Rafalski, M ^{[1
]}

Kasireddy-Polam, P ^{[1
]}

Wong, H ^{[1
]}

Molski, TF ^{[1
]}

Zhang, G ^{[1
]}

Li, YW ^{[1
]}

Lelas, S ^{[1
]}

Peng, Y ^{[1
]}

McElroy, JF ^{[1
]}

Zaczek, RC ^{[1
]}

Taub, RA ^{[1
]}

Combs, AP ^{[1
]}

Gilligan, PJ ^{[1
]}

Trainor, GL ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Wallingford, CT 06492 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 23期

关键词：

D O I：

10.1021/jm049737f

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Corticotropin releasing factor (CRF) is the primary regulator of the hypothalamus-pituitary-adrenal (HPA) axis, coordinating the endocrine, behavioral, and autonomic responses to stress. It has been postulated that small molecules that can antagonize the binding of CRF, to its receptor may serve as a treatment for anxiety-related and/or affective disorders. Members within a series of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones, exemplified by compound 2 (IC50 = 0.70 nM), were found to be very potent antagonists of CRF1. Compound 8w showed high CRF1 receptor binding affinity and was examined further in vivo. The compound was efficacious in a defensive withdrawal model of anxiety in rats and had a long half-life and reasonable oral bioavailability in dog pharmacokinetic studies.

引用

页码：5783 / 5790

页数：8

共 34 条

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