Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity

详细信息    查看全文

• 作者：Chen Chen ; Yongsheng Chen ; Joseph Pontillo ; Zhiqiang Guo ; Charles Q. Huang ; Dongpei Wu ; Ajay Madan ; Takung Chen ; Jenny Wen ; Qiu Xie ; Fabio C. Tucci ; Martin Rowbottom ; Yun-Fei Zhu ; Warren Wade ; John Sa
• 关键词：Zwitterion ; Gonadotropin-releasing hormone ; Receptor ; Antagonist ; CYP3A4 ; Inhibition ; Structure– ; activity relationship
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 出版时间：1 June 2008
• 年：2008
• 卷：18
• 期：11
• 页码：3301-3305
• 全文大小：131 K

文摘

Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K_i of 2.2 nM at GnRH-R and an IC₅₀ of 36 μM at CYP3A4.