Orally bioavailable, indole-based nonpeptide GnRH receptor antagonists with high potency and functional activity.
Stereospecific introduction of a methyl group to the indole-3-side chain enhanced activity in our tryptamine-derived series of GnRH receptor antagonists. Further improvements were achieved by variation of the bicyclic amino moiety of the tertiary amide and by adjustment of the tether length to a pyridine or pyridone terminus. These modifications culminated in analogue 24, which had oral activity in a rat model and acceptable oral bioavailability and half-life in dogs and monkeys.
Ashton
W T
WT
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, NJ 07065-0900, Rahway, USA
Sisco
R M
RM
Kieczykowski
G R
GR
Yang
Y T
YT
Yudkovitz
J B
JB
Cui
J
J
Mount
G R
GR
Ren
R N
RN
Wu
T J
TJ
Shen
X
X
Lyons
K A
KA
Mao
A H
AH
Carlin
J R
JR
Karanam
B V
BV
Vincent
S H
SH
Cheng
K
K
Goulet
M T
MT
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000378:metabolism; D008253:Macaca mulatta; D023421:Models, Animal; D051381:Rats; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
D007211:Indoles; D011966:Receptors, LHRH; D014363:Tryptamines; D007986:Luteinizing Hormone