New bicyclic cannabinoid receptor-1 (CB₁-R) antagonists

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• 作者：Philip A. Carpino ; David A. Griffith ; Subas Sakya ; Robert L. Dow ; Shawn C. Black ; John R. Hadcock ; Philip A. Iredale ; Dennis O. Scott ; Michael W. Fichtner ; Colin R. Rose et al.
• 关键词：Cannabinoid receptor antagonists ; CB1-R ; 2 ; 6-Dihydro-pyrazolo[ ; 4 ; 3-d] ; pyrimidin-7-one ; 2 ; 6-Dihydro-pyrazolo[ ; 3 ; 4-c] ; pyridin-7-one ; 2 ; 6-Dihydro-pyrazolo[ ; 3 ; 4-d] ; pyridazin-7-one ; 1 ; 9-Dihydro-purin-6-one ; Obesity
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2006
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 February 2006
• 卷：16
• 期：3
• 页码：731-736
• 文件大小：194 K

摘要

A series of conformationally constrained bicyclic derivatives derived from SR141716 was prepared and evaluated as hCB₁-R antagonists and inverse agonists. Optimization of the structure–activity relationships around the 2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one derivative 2a led to the identification of two compounds with oral activity in rodent feeding models (2h and 4a). Replacement of the PP group in 2h with other bicyclic groups resulted in a loss of binding affinity.