3-(2-aminoalkyl)-1-(2,6-difluorobenzyl)-5- (2-fluoro-3-methoxyphenyl)-6-methyl-uracils as orally bioavailable antagonists of the human gonadotropin releasing hormone receptor.
Uracils possessing N-3 side chains derived from various amino alcohols were designed and synthesized as potent human gonadotropin releasing hormone receptor antagonists. The compounds herein presented displayed superior metabolic stability than their predecessor molecules. Selected compounds from this series featured good oral bioavailability in mice and cynomolgus monkeys.
Tucci
Fabio C
FC
Departments of Medicinal Chemistry, Endocrinology, and Preclinical Development, 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
Gao
Yinghong
Y
Rowbottom
Martin W
MW
Struthers
R Scott
RS
Reinhart
Greg J
GJ
Xie
Qiu
Q
Chen
Ta Kung
TK
Bozigian
Haig
H
Killam Bonneville
Anne L
AL
Fisher
Andrew
A
Jin
Liping
L
Saunders
John
J
Chen
Chen
C
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D011974:Receptors, LH / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D011974:Receptors, LH; D014498:Uracil