title: 5-Aryluracils as potent GnRH antagonists-Characterization of atropisomers.
abstract: Optimization of a series of uracils bearing a 2-fluoro- or 2-chloro-3-methoxyphenyl group at the 5-position resulted in compounds such as 3d and 3f with subnanomolar binding affinity at the human GnRH receptor. While the 2-fluoro-3-methoxyphenyl compound 3a was characterized as a mixture of interchangeable atropisomers, the diastereoisomers of 2-chloro-3-methoxyphenyl analogs were separated. It was found that the aR-atropisomer was much more potent than the aS-isomer based on the X-ray crystal structure of 3h-II.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92129, USA.
authors.forename: Liren
authors.initials: L
authors.lastname: Zhao
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Hu
authors.forename: Dongpei
authors.initials: D
authors.lastname: Wu
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Zhu
authors.forename: Martin
authors.initials: M
authors.lastname: Rowbottom
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Gross
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: R Scott
authors.initials: RS
authors.lastname: Struthers
authors.forename: Qiu
authors.initials: Q
authors.lastname: Xie
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011966:Receptors, LHRH; D014498:Uracil