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.
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).
Tucci
Fabio C
FC
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA. ftucci@neurocrine.com
Zhu
Yun-Fei
YF
Guo
Zhiqiang
Z
Gross
Timothy D
TD
Connors
Patrick J
PJ
Struthers
R Scott
RS
Reinhart
Greg J
GJ
Saunders
John
J
Chen
Chen
C
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*
D011966:Receptors, LHRH; D014498:Uracil; C008378:6-methyluracil