Identification of 1-arylmethyl-3- (2-aminoethyl)-5-aryluracil as novel gonadotropin-releasing hormone receptor antagonists.
Based on SAR from bicyclic GnRH antagonists such as 6-aminomethyl-7-arylpyrrolo[1,2-a]pyrimid-4-ones (1) and 2-aryl-3-aminomethylimidazolo[1,2-a]pyrimid-5-ones (2a,b), a series of novel uracil compounds (4) were derived as the GnRH antagonists. Their syntheses and initial SAR are discussed herein. This is the first time that monocycle-based GnRH receptor antagonists are reported.
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, California 92121, USA. fzhu@neurocrine.com
Yun-Fei
YF
Zhu
Timothy D
TD
Gross
Zhiqiang
Z
Guo
Patrick J
PJ
Connors
Yinghong
Y
Gao
Fabio C
FC
Tucci
R Scott
RS
Struthers
Greg J
GJ
Reinhart
John
J
Saunders
Ta Kung
TK
Chen
Anne L
AL
Killam Bonneville
Chen
C
Chen
D000818:Animals; D004355:Drug Stability; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008657:Metabolic Clearance Rate; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014498:Uracil / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D007093:Imidazoles; D011758:Pyrroles; D011966:Receptors, LHRH; D014498:Uracil