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

• Published in: Journal of medicinal chemistry 2009-12, Vol.52 (23), p.7544-7569
• Main Authors: Jain, Nareshkumar, Xu, Jiayi, Kanojia, Ramesh M, Du, Fuyong, Jian-Zhong, Guo, Pacia, Emmanuel, Lai, Muh-Tsann, Musto, Amy, Allan, George, Reuman, Michael, Li, Xun, Hahn, DoWon, Cousineau, Martin, Peng, Sean, Ritchie, David, Russell, Ronald, Lundeen, Scott, Sui, Zhihua
• Format: Article
• Language: English
• Subjects: Animals; Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - pharmacology; Benzopyrans - therapeutic use; Biological and medical sciences; Bone Resorption - drug therapy; Cell Line, Tumor; Cholesterol - blood; Drug Evaluation, Preclinical; Drug Stability; Epithelial Cells - drug effects; Epithelial Cells - pathology; Female; Hormones. Endocrine system; Hot Flashes - drug therapy; Humans; Medical sciences; Organ Size - drug effects; Ovariectomy; Pharmacology. Drug treatments; Postmenopause - blood; Postmenopause - drug effects; Rats; Receptors, Estrogen - metabolism; Selective Estrogen Receptor Modulators - chemical synthesis; Selective Estrogen Receptor Modulators - chemistry; Selective Estrogen Receptor Modulators - pharmacology; Selective Estrogen Receptor Modulators - therapeutic use; Structure-Activity Relationship; Substrate Specificity; Uterus - pathology; Vagina - drug effects; Vagina - secretion
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900146e

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 IC50 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).