Synthesis and structure-activity relationships of 1-arylmethyl-3-(2-aminopropyl)-5-aryl-6-methyluracils as potent GnRH receptor antagonists.
The novel synthesis and SAR studies of 6-methyluracils as human GnRH receptor antagonists are discussed. Introduction of a small methyl substituent at the beta-position from N3 of the uracil improved the GnRH binding potency by 5- to 10-fold. The best compound from the series had binding affinity of 5 nM (K(i)) to the human GnRH receptor.
Guo
Zhiqiang
Z
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA. zguo@neurocrine.com
Zhu
Yun-Fei
YF
Tucci
Fabio C
FC
Gao
Yinghong
Y
Struthers
R Scott
RS
Saunders
John
J
Gross
Timothy D
TD
Xie
Qiu
Q
Reinhart
Greg J
GJ
Chen
Chen
C
D004305:Dose-Response Relationship, Drug; D006801:Humans; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000502:physiology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*
D011966:Receptors, LHRH; D014498:Uracil; C008378:6-methyluracil