Identification and structure-activity relationships of chromene-derived selective estrogen receptor modulators for treatment of postmenopausal symptoms.
As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
Johnson & Johnson Pharmaceutical Research & Development LLC, 665 Stockton Drive, Exton, Pennsylvania 19341, USA. njain@TCRS-US.com
Nareshkumar
N
Jain
Jiayi
J
Xu
Ramesh M
RM
Kanojia
Fuyong
F
Du
Guo
G
Jian-Zhong
Emmanuel
E
Pacia
Muh-Tsann
MT
Lai
Amy
A
Musto
George
G
Allan
Michael
M
Reuman
Xun
X
Li
Dowon
D
Hahn
Martin
M
Cousineau
Sean
S
Peng
David
D
Ritchie
Ronald
R
Russell
Scott
S
Lundeen
Zhihua
Z
Sui
D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001862:Bone Resorption / Q000188:drug therapy; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D019584:Hot Flashes / Q000188:drug therapy; D006801:Humans; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D017698:Postmenopause / Q000097:blood / Q000187:drug effects*; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014599:Uterus / Q000473:pathology; D014621:Vagina / Q000187:drug effects / Q000378:metabolism
D001578:Benzopyrans; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D002784:Cholesterol