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Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity |
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| Authors: | Chen Chen Chen Yongsheng Pontillo Joseph Guo Zhiqiang Huang Charles Q Wu Dongpei Madan Ajay Chen Takung Wen Jenny Xie Qiu Tucci Fabio C Rowbottom Martin Zhu Yun-Fei Wade Warren Saunders John Bozigian Haig Struthers R Scott |
| Affiliation: | Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA. cchen@neurocrine.com |
| Abstract: | 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 IC(50) of 36 microM at CYP3A4. |
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