Bioorganic & Medicinal Chemistry Letters 2004-05-03

Synthesis and structure-activity relationships of (R)-1-alkyl-3-[2-(2-amino)phenethyl]-5-(2-fluorophenyl)-6-methyluracils as human GnRH receptor antagonists.

Martin W Rowbottom, Fabio C Tucci, Yun-Fei Zhu, Zhiqiang Guo, Timothy D Gross, Greg J Reinhart, Qui Xie, R Scott Struthers, John Saunders, Chen Chen

Index: Bioorg. Med. Chem. Lett. 14(9) , 2269-74, (2004)

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Abstract

The synthesis of a series of (R)-1-alkyl-3-[2-(2-amino)phenethyl]-5-(2-fluorophenyl)-6-methyluracils is discussed. SAR around N-1 of the uracil was explored, which led to the discovery that an electron-deficient 2,6-disubstituted benzyl group is required for optimal receptor binding. The best compound from the series had binding affinity of 0.7 nM (K(i) for the human GnRH receptor, which was 8-fold better than the 2,6-difluorobenzyl analog.