Identification and Structure−Activity Relationships of Chromene-Derived Selective Estrogen Receptor Modulators for Treatment of Postmenopausal Symptoms

Abstract

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).

Development of the β-lactam type molecular scaffold for selective estrogen receptor α modulator action: synthesis and cytotoxic effects in MCF-7 breast cancer cells

“…The recently reported benzopyranobenzoxepanes were identified as potent SERMs for the treatment of postmenopausal symptoms 31 . We are specifically interested in the development of novel heterocyclic ring scaffolds as ER antagonists 32 .…”

Crystal structure of 3-amino-9-methoxy-1-phenyl-1H-benzo[f]chromene-2-carbonitrile, C21H16N2O2

“…Chromene and benzochromene derivatives have attracted considerable interest owing to their biological and pharmaceutical activities such as antibacterial [1][2][3], antifungal [4][5][6], vascular-disrupting [7], antioxidant [8,9], anticancer [10][11][12][13], estrogenic anticoagulant and antispasmolytic [14], antileishmanial [15], antiproliferative and apoptosis inducing [16][17][18][19].…”

A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

“…A common adverse event associated with SERMs to date seems to be an increased incidence of hot flushes and warrants further study to determine a solution. There are several novel agents being evaluated to address hot flashes [207][208][209][210]. Bazedoxifene has been shown to maintain or increase BMD, reduce bone turnover, and decrease the risk of new vertebral fracture in postmenopausal women without evidence of endometrial or breast stimulation in large, prospective phase III studies [196][197][198].…”