5-Aryluracils as potent GnRH antagonists-Characterization of atropisomers.
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.
Zhao
Liren
L
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92129, USA.
Guo
Zhiqiang
Z
Chen
Yongsheng
Y
Hu
Tao
T
Wu
Dongpei
D
Zhu
Yun-Fei
YF
Rowbottom
Martin
M
Gross
Timothy D
TD
Tucci
Fabio C
FC
Struthers
R Scott
RS
Xie
Qiu
Q
Chen
Chen
C
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*
D011966:Receptors, LHRH; D014498:Uracil