Synthesis and structure-activity relationships of 1-benzylindane derivatives as selective agonists for estrogen receptor beta.
The estrogen receptor beta (ERβ) selective agonist is considered a promising candidate for the treatment of estrogen deficiency symptoms in ERβ-expressing tissues, without the risk of breast cancer, and multiple classes of compounds have been reported as ERβ selective agonists. Among them, 6-6 bicyclic ring-containing structures (e.g., isoflavone phytoestrogens) are regarded as one of the cyclized analogues of isobutestrol 5b, and suggest that other cyclized scaffolds comprising 5-6 bicyclic rings could also act as selective ERβ ligands. In this study, we evaluated the selective ERβ agonistic activity of 1-(4-hydroxybenzyl)indan-5-ol 7a and studied structure-activity relationship (SAR) of its derivatives. Some functional groups improved the properties of 7a; introduction of a nitrile group on the indane-1-position resulted in higher selectivity for ERβ (12a), and further substitution with a fluoro or a methyl group to the pendant phenyl ring was also preferable (12b, d, and e). Subsequent chiral resolution of 12a identified that R-12a has a superior profile over S-12a. This is comparable to diarylpropionitrile (DPN) 5c, one of the promising selective ERβ agonists and indicates that this indane-based scaffold has the potential to provide better ERβ agonistic probes.
Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., 4365-1, Hotakakashiwabara, Azumino, Nagano 399-8304, Japan. Electronic address: shigeru_yonekubo@pharm.kissei.co.jp.
Shigeru
S
Yonekubo
Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., 4365-1, Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
Nobuhiko
N
Fushimi
Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., 4365-1, Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
Takashi
T
Miyagi
Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., 4365-1, Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
Osamu
O
Nakanishi
Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., 4365-1, Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
Kenji
K
Katsuno
Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., 4365-1, Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
Motoyasu
M
Ozawa
Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., 4365-1, Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
Chiaki
C
Handa
Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., 4365-1, Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
Noritaka
N
Furuya
Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., 4365-1, Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
Hideyuki
H
Muranaka
D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007189:Indans; D008024:Ligands
ERβ; ERβ agonist; ERβ ligand; Estrogen receptor