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

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 Saunders,Haig Bozigian,R Scott Struthers

Bioorganic & Medicinal Chemistry Letters（2008）

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摘要

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 Ki of 2.2nM at GnRH-R and an IC50 of 36μM at CYP3A4.

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关键词

Zwitterion,Gonadotropin-releasing hormone,Receptor,Antagonist,CYP3A4,Inhibition,Structure–activity relationship

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