Synthesis and structure-activity relationships of (R)-1-alkyl-3-[2-(2-amino)phenethyl]-5-(2-fluorophenyl)-6-methyluracils as human GnRH receptor antagonists.
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.
Rowbottom
Martin W
MW
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, CA 92121, USA. mrowbottom@neurocrine.com
Tucci
Fabio C
FC
Zhu
Yun-Fei
YF
Guo
Zhiqiang
Z
Gross
Timothy D
TD
Reinhart
Greg J
GJ
Xie
Qui
Q
Struthers
R Scott
RS
Saunders
John
J
Chen
Chen
C
D006801:Humans; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D011966:Receptors, LHRH; D014498:Uracil; C008378:6-methyluracil