Synthesis and biological evaluation of novel thio-substituted chromanes as high-affinity partial agonists for the estrogen receptor.
Synthesis of (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-piperidinoethanethio)phenyl)chromane (13) and (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethanethio)phenyl)chromane (15) is presented. These compounds are representatives of a novel class of compounds with high in vitro binding affinity for the estrogen receptor (IC(50)=7-10 nM), and very low in vitro uterotrophic activity (max stim.=5-17% rel to moxestrol; EC(50)=0.5-1.8 nM).
Christiansen
Lise B
LB
Health Care Discovery & Preclinical Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark. libc@novonordisk.com
Wenckens
Martin
M
Bury
Paul S
PS
Gissel
Birgitte
B
Hansen
Birgit S
BS
Thorpe
Susan M
SM
Jacobsen
Poul
P
Kanstrup
Anders
A
Jørgensen
Anker S
AS
Naerum
Lars
L
Wassermann
Karsten
K
D000818:Animals; D001667:Binding, Competitive; D002839:Chromans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004717:Endometrium / Q000166:cytology / Q000187:drug effects; D004958:Estradiol / Q000378:metabolism; D005260:Female; D011817:Rabbits; D011960:Receptors, Estrogen / Q000819:agonists*; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D002839:Chromans; D011960:Receptors, Estrogen; D013457:Sulfur Compounds; D004958:Estradiol