Synthesis and structure-activity relationships of uracil derived human GnRH receptor antagonists: (R)-3-[2-(2-amino)phenethyl]-1-(2,6-difluorobenzyl)-6-methyluracils containing a substituted thiophene or thiazole at C-5 |
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| Authors: | Rowbottom Martin W Tucci Fabio C Connors Patrick J Gross Timothy D Zhu Yun-Fei Guo Zhiqiang Moorjani Manisha Acevedo Oscar Carter Lee Sullivan Susan K Xie Qiu Fisher Andrew Struthers R Scott Saunders John Chen Chen |
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| Institution: | Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA. mrowbottom@neurocrine.com |
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| Abstract: | The synthesis of a series of (R)-3-2-(2-amino)phenethyl]-1-(2,6-difluorobenzyl)-6-methyluracils containing a substituted thiophene or thiazole at C-5 is described. SAR around C-5 of the uracil led to the discovery that a 2-thienyl or (2-phenyl)thiazol-4-yl group is required for optimal receptor binding. The best compound from the series had a binding affinity of 2 nM (K(i)) for the human GnRH receptor. A novel and convenient preparation of N-1-(2,6-difluorobenzyl)-6-methyluracil is also described. |
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