8-(4-Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: Selective and Centrally Active Corticotropin-Releasing Factor Receptor-1 (CRF1) Antagonists

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• 作者：Paul J. Gilligan ; Liqi He ; Todd Clarke ; Parcharee Tivitmahaisoon ; Snjezana Lelas ; Yu-Wen Li ; Karen Heman ; Lawrence Fitzgerald ; Keith Miller ; Ge Zhang ; Anne Marshall ; Carol Krause ; John McElroy ; Kathyr
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 14, 2009
• 年：2009
• 卷：52
• 期：9
• 页码：3073-3083
• 全文大小：176K
• 年卷期：v.52,no.9(May 14, 2009)
• ISSN：1520-4804

文摘

This report describes the syntheses and structure−activity relationships of 8-(4-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF₁) receptor antagonists. CRF₁ receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discovery of analogue 12-3, which is a potent, selective CRF₁ antagonist (hCRF₁ IC₅₀ = 4.7 ± 2.0 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 12-3 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 12-3 has been advanced to clinical trials.