Discovery of N-(1-Ethylpropyl)-[3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl)-6-methyl-pyrazin-2-yl]amine 59 (NGD 98鈭?): An Orally Active Corticotropin Releasing Factor-1 (CRF-1) Rece

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• 作者：Kevin J. Hodgetts ; Ping Ge ; Taeyoung Yoon ; Ste虂phane De Lombaert ; Robbin Brodbeck ; Michael Gulianello ; Andrzej Kieltyka ; Raymond F. Horvath ; John H. Kehne ; James E. Krause ; George D. Maynard ; Diane Hoffman ; Younglim Lee ; Laurence Fung ; Dario Doller
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 23, 2011
• 年：2011
• 卷：54
• 期：12
• 页码：4187-4206
• 全文大小：1333K
• 年卷期：v.54,no.12(June 23, 2011)
• ISSN：1520-4804

文摘

The design, synthesis, and structure鈭抋ctivity relationships of a novel series of pyrazines, acting as corticotropin releasing factor-1 (CRF-1) receptor antagonists, are described. Synthetic methodologies were developed to prepare a number of substituted pyrazine cores utilizing regioselective halogenation and chemoselective derivatization. Noteworthy, an efficient 5-step synthesis was developed for the lead compound 59 (NGD 98鈭?), which required no chromatography. Compound 59 was characterized as an orally bioavailable, brain penetrant, and highly selective CRF-1 receptor antagonist. Occupancy of rat brain CRF-1 receptors was quantified using ex vivo receptor occupancy assays, using both brain tissue homogenates as well as brain slices receptor autoradiography. Behaviorally, oral administration of 59 significantly antagonized CRF-induced locomotor activity at doses as low as 10 mg/kg and dose-dependently reduced the restraint stress-induced ACTH increases.