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

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