title: Synthesis and structure-activity relationships of 1-arylmethyl-3-(2-aminopropyl)-5-aryl-6-methyluracils as potent GnRH receptor antagonists.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA. zguo@neurocrine.com
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Zhu
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Gao
authors.forename: R Scott
authors.initials: RS
authors.lastname: Struthers
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Gross
authors.forename: Qiu
authors.initials: Q
authors.lastname: Xie
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Reinhart
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: 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*
chemical_list: D011966:Receptors, LHRH; D014498:Uracil; C008378:6-methyluracil