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3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)- 6-methylpyrimidin-2,4-dione (NBI 42902) as a Potent and Orally Active Antagonist of the Human Gonadotropin-Releasing Hormone Receptor. Design, Synthesis, and in Vitro and in Vivo Characterization

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journal contribution
posted on 24.02.2005, 00:00 by Fabio C. Tucci, Yun-Fei Zhu, R. Scott Struthers, Zhiqiang Guo, Timothy D. Gross, Martin W. Rowbottom, Oscar Acevedo, Yinghong Gao, John Saunders, Qiu Xie, Greg J. Reinhart, Xin-Jun Liu, Nicholas Ling, Anne K. L. Bonneville, Takung Chen, Haig Bozigian, Chen
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 human gonadotropin-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 a potent 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-13b had good plasma exposure in cynomolgus monkeys after oral administration, with a Cmax of 737 ng/mL and an AUC of 2392 ng/mL·h at a 10 mg/kg dose. Moreover, oral administration of R-13b to castrated male cynomolgus monkeys resulted in a significant decrease in serum levels of luteinizing hormone. These results demonstrate that compounds from this series of uracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhuman primates.