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.
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.
Rowbottom
Martin W
MW
Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA. mrowbottom@neurocrine.com
Tucci
Fabio C
FC
Connors
Patrick J
PJ
Gross
Timothy D
TD
Zhu
Yun-Fei
YF
Guo
Zhiqiang
Z
Moorjani
Manisha
M
Acevedo
Oscar
O
Carter
Lee
L
Sullivan
Susan K
SK
Xie
Qiu
Q
Fisher
Andrew
A
Struthers
R Scott
RS
Saunders
John
J
Chen
Chen
C
D006801:Humans; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles; D013876:Thiophenes; D014498:Uracil / Q000031:analogs & derivatives*
D011966:Receptors, LHRH; D013844:Thiazoles; D013876:Thiophenes; D014498:Uracil