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