A new series of estrogen receptor modulators: effect of alkyl substituents on receptor-binding affinity.
New types of selective estrogen receptor modulators (SERMs) were synthesized and evaluated for their binding affinity and biological effect on reproductive cells. A proposed lead structure (B) was derivatized to provide compounds 30 and 44, which showed good estrogen-receptor binding affinity (K(i) values: 6.3 and 10 nM, respectively), as well as minimal impact on mammary and uterine carcinoma cells. Introduction of an alkyl group in the core structure considerably enhanced receptor-binding affinity of the compounds tested. Synthesis and structure-activity relationships of these compounds are described.
Kamada
Atsushi
A
Tsukuba Research Laboratories, Eisai Co., Ltd.
Sasaki
Atsushi
A
Kitazawa
Noritaka
N
Okabe
Tadashi
T
Nara
Kazumasa
K
Hamaoka
Shinichi
S
Araki
Shin
S
Hagiwara
Hiroaki
H
D000469:Alkaline Phosphatase / Q000378:metabolism; D000478:Alkylation; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D004958:Estradiol / Q000378:metabolism; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
D007202:Indicators and Reagents; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D004958:Estradiol; D000469:Alkaline Phosphatase