title: 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.
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.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, 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: Patrick J
authors.initials: PJ
authors.lastname: Connors
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Gross
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Zhu
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: Manisha
authors.initials: M
authors.lastname: Moorjani
authors.forename: Oscar
authors.initials: O
authors.lastname: Acevedo
authors.forename: Lee
authors.initials: L
authors.lastname: Carter
authors.forename: Susan K
authors.initials: SK
authors.lastname: Sullivan
authors.forename: Qiu
authors.initials: Q
authors.lastname: Xie
authors.forename: Andrew
authors.initials: A
authors.lastname: Fisher
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; D013844:Thiazoles; D013876:Thiophenes; D014498:Uracil / Q000031:analogs & derivatives*
chemical_list: D011966:Receptors, LHRH; D013844:Thiazoles; D013876:Thiophenes; D014498:Uracil