| Abstract
| - Further structure−activity relationship studies of a series of substituted uracils at the 1, 3,and 5 positions resulted in the discovery of several potent antagonists of the humangonadotropin-releasing hormone receptor. Uracils bearing a side chain derived from phenylglycinol at the 3-position were shown to be orally bioavailable in monkeys. 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione (R-13b, NBI 42902) displayed subnanomolar binding affinity (Ki = 0.56 nM) and was apotent functional antagonist (IC50 = 3.0 nM in Ca2+ flux assay) at the human GnRH receptor.It also bound to the monkey GnRH receptor with high affinity (Ki = 3.9 nM). In addition, R-13bhad good plasma exposure in cynomolgus monkeys after oral administration, with a Cmax of737 ng/mL and an AUC of 2392 ng/mL·h at a 10 mg/kg dose. Moreover, oral administrationof R-13b to castrated male cynomolgus monkeys resulted in a significant decrease in serumlevels of luteinizing hormone. These results demonstrate that compounds from this series ofuracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhumanprimates.
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