3,4-二氢-1H-吡啶并[2,3-b]吡嗪-2-酮作为促肾上腺皮质激素释放因子-1受体拮抗剂的合成、构效关系及体内性质

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.

作者信息

Dzierba Carolyn D, Takvorian Amy G, Rafalski Maria, Kasireddy-Polam Padmaja, Wong Harvey, Molski Thaddeus F, Zhang Ge, Li Yu-Wen, Lelas Snjezana, Peng Yong, McElroy John F, Zaczek Robert C, Taub Rebecca A, Combs Andrew P, Gilligan Paul J, Trainor George L

机构信息

Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492, USA.

出版信息

J Med Chem. 2004 Nov 4;47(23):5783-90. doi: 10.1021/jm049737f.

DOI:10.1021/jm049737f

PMID:15509177

Abstract

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 CRF1 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.

摘要

促肾上腺皮质激素释放因子（CRF）是下丘脑-垂体-肾上腺（HPA）轴的主要调节因子，协调对压力的内分泌、行为和自主反应。据推测，能够拮抗CRF1与其受体结合的小分子可能可用作治疗焦虑相关和/或情感障碍的药物。在一系列3,4-二氢-1H-吡啶并[2,3-b]吡嗪-2-酮中，以化合物2（IC50 = 0.70 nM）为例的成员被发现是非常有效的CRF1拮抗剂。化合物8w表现出高CRF1受体结合亲和力，并在体内进行了进一步研究。该化合物在大鼠焦虑防御性回避模型中有效，并且在犬药代动力学研究中具有长半衰期和合理的口服生物利用度。