Discovery of thiochroman and chroman derivatives as pure antiestrogens and their structure-activity relationship.
In order to develop pure antiestrogens, a series of 7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman and 7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman derivatives with sulfoxide containing side chains at the 4-position were designed, synthesized, and evaluated. Among them, compounds 14b and 24b functioned as pure antiestrogens with the ability to downregulate ER, and their in vitro and in vivo antiestrogen activities were similar to those of ICI182,780. In addition, the structure-activity relationship indicated that the (3RS,4RS)-configuration between the 3- and 4-position, the methyl group at the 3-position, the 9-methylene chain between the scaffold and the sulfoxide moiety, and the terminal perfluoroalkyl moiety play an important role in increasing estrogen receptor binding and oral antiestrogen activities.
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd, 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan. kanbeyst@chugai-pharm.co.jp
Yoshitake
Y
Kanbe
Myung-Hwa
MH
Kim
Masahiro
M
Nishimoto
Yoshihito
Y
Ohtake
Nobuaki
N
Kato
Toshiaki
T
Tsunenari
Kenji
K
Taniguchi
Iwao
I
Ohizumi
Shin-ichi
S
Kaiho
Kazumi
K
Morikawa
Jae-Chon
JC
Jo
Hyun-Suk
HS
Lim
Hak-Yeop
HY
Kim
D000818:Animals; D001667:Binding, Competitive; D002839:Chromans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects
D002839:Chromans; D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen; C074283:estradiol 3-benzoate; D004958:Estradiol