Modification of the pyridine moiety of non-peptidyl indole GnRH receptor antagonists.
The synthesis of a number of indole GnRH antagonists is described. Oxidation of the pyridine ring nitrogen, combined with alkylation at the two position, led to a compound with an excellent in vitro activity profile as well as oral bioavailability in both rats and dogs.
Simeone
Joseph P
JP
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA. joe_simeone@merck.com
Bugianesi
Robert L
RL
Ponpipom
Mitree M
MM
Yang
Yi Tien
YT
Lo
Jane-Ling
JL
Yudkovitz
Joel B
JB
Cui
Jisong
J
Mount
George R
GR
Ren
Rena Ning
RN
Creighton
Mellissa
M
Mao
An-Hua
AH
Vincent
Stella H
SH
Cheng
Kang
K
Goulet
Mark T
MT
D000284:Administration, Oral; D000478:Alkylation; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D006207:Half-Life; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D010084:Oxidation-Reduction; D011725:Pyridines / Q000737:chemistry; D051381:Rats; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D007211:Indoles; D011725:Pyridines; D011966:Receptors, LHRH; C023666:pyridine