Identification of neutral 4-O-alkyl quinolone nonpeptide GnRH receptor antagonists.
A series of neutral, nonbasic quinolone GnRH antagonists were prepared via Mitsunobu alkylation of protected and unprotected 4-hydroxy quinolone intermediates. The synthetic route was improved by utilization of unique reactivity and convergency afforded by the use of mono and bis-trimethylsilylethyl protected quinolones. Potent neutral GnRH antagonists were identified, including ether and lactam derivatives, that show similar in vitro binding affinity and functional activity as compared to the earlier basic 4-aminoalkyl quinolone series of nonpeptide GnRH antagonists.
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. robert_devita@merck.com
Robert J
RJ
DeVita
Mamta
M
Parikh
Jinlong
J
Jiang
Jason A
JA
Fair
Jonathan R
JR
Young
Thomas F
TF
Walsh
Mark T
MT
Goulet
Jane-L
JL
Lo
Ning
N
Ren
Joel B
JB
Yudkovitz
Jisong
J
Cui
Yi T
YT
Yang
Kang
K
Cheng
Susan P
SP
Rohrer
Matthew J
MJ
Wyvratt
D006801:Humans; D015394:Molecular Structure; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
D015363:Quinolones; D011966:Receptors, LHRH