title: Synthesis and structure-activity relationships of 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils as antagonists of the human GnRH Receptor.
abstract: A new class of small molecule GnRH antagonists, the 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils, was designed and a novel stereoselective synthesis for these compounds was developed. The stereochemical integrities of key intermediates (S)-6 and (R)-6 were confirmed by a combination of X-ray crystallography and chiral HPLC determinations. SAR studies were performed, which allowed the identification of derivatives (R)-9f, (R)-9h and (R)-12 as potent hGnRH antagonists (K(i)=20 nM).
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA. ftucci@neurocrine.com
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Zhu
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Gross
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Connors
authors.forename: R Scott
authors.initials: RS
authors.lastname: Struthers
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Reinhart
authors.forename: John
authors.initials: J
authors.lastname: Saunders
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; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D011966:Receptors, LHRH; D014498:Uracil; C008378:6-methyluracil