Investigation of the 4-O-alkylamine substituent of non-peptide quinolone GnRH receptor antagonists.
Synthesis and in vitro activity of the enantiomers of quinolone GnRH antagonist (+/-)-1 are reported. Chiral amino alcohols were prepared from the appropriate cyclic D- or L-amino acids by the Amdt-Eistert homologation followed by reduction of the resulting esters. Incorporation of these pharmacophores was achieved via a novel Mitsunobu alkylation of 4-hydroxyquinolones. The key amine pharmacophore for binding to the rat GnRH receptor was most active in the S-configuration. Ring size was not important for potency with 4, 5, 6, and 7-membered ring amines exhibiting similar potency.
DeVita
R J
RJ
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA.
Goulet
M T
MT
Wyvratt
M J
MJ
Fisher
M H
MH
Lo
J L
JL
Yang
Y T
YT
Cheng
K
K
Smith
R G
RG
D000818:Animals; D011485:Protein Binding; D015363:Quinolones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism
D015363:Quinolones; D011966:Receptors, LHRH