2-Arylindoles as gonadotropin releasing hormone (GnRH) antagonists: optimization of the tryptamine side chain.
A series of 2-arylindoles containing novel heteroaromatic substituents on the tryptamine tether, based on compound 1, was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. Successful modifications of 1 included chain length variation (reduction) and replacement of the pyridine with heteroaromatic groups. These alterations culminated in the discovery of compound 27kk which had excellent in vitro potency and oral efficacy in rodents.
Young
Jonathan R
JR
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, NJ Rahway 07065-0900, USA. young@merck.com
Huang
Song X
SX
Walsh
Thomas F
TF
Wyvratt
Matthew J
MJ
Yang
Yi Tien
YT
Yudkovitz
Joel B
JB
Cui
Jisong
J
Mount
George R
GR
Ren
Rena Ning
RN
Wu
Tsuei Ju
TJ
Shen
Xiaolan
X
Lyons
Kathryn A
KA
Mao
An Hua
AH
Carlin
Josephine R
JR
Karanam
Bindhu V
BV
Vincent
Stella H
SH
Cheng
Kang
K
Goulet
Mark T
MT
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D002064:Buserelin / Q000378:metabolism; D005300:Fertility Agents, Female / Q000037:antagonists & inhibitors*; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000737:chemistry*
D005300:Fertility Agents, Female; D007211:Indoles; D007295:Inositol Phosphates; D011804:Quinolines; D014363:Tryptamines; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D002064:Buserelin