Bioorganic & Medicinal Chemistry Letters 2003-10-06

Synthesis and structure-activity relationships of 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils as antagonists of the human GnRH Receptor.

Fabio C Tucci, Yun-Fei Zhu, Zhiqiang Guo, Timothy D Gross, Patrick J Connors, R Scott Struthers, Greg J Reinhart, John Saunders, Chen Chen

Index: Bioorg. Med. Chem. Lett. 13(19) , 3317-22, (2003)

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Abstract

A new class of small molecule GnRH antagonists, the 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils, was designed and a novel stereoselective synthesis for these compounds was developed. The stereochemical integrities of key intermediates (S)-6 and (R)-6 were confirmed by a combination of X-ray crystallography and chiral HPLC determinations. SAR studies were performed, which allowed the identification of derivatives (R)-9f, (R)-9h and (R)-12 as potent hGnRH antagonists (K(i)=20 nM).