Benzothiophene and naphthalene derived constrained SERMs

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 20; pp. 5103 - 5106
• Main Authors: Wallace, Owen B., Bryant, Henry U., Shetler, Pamela K., Adrian, Mary D., Geiser, Andrew G.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 18.10.2004; Elsevier
• Subjects: Animals; Biological and medical sciences; Cell Line; Chromatography, High Pressure Liquid; Female; Hormones. Endocrine system; Humans; Ligands; Medical sciences; Miscellaneous; Naphthalenes - chemical synthesis; Naphthalenes - chemistry; Naphthalenes - pharmacology; Pharmacology. Drug treatments; Radioligand Assay; Rats; Selective Estrogen Receptor Modulators - chemical synthesis; Selective Estrogen Receptor Modulators - chemistry; Selective Estrogen Receptor Modulators - pharmacology; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Uterus - drug effects; Uterus - physiology; Modulator; Ligand; Selectivity; Estradiol; In vitro; Naphthalene derivatives; Biological activity; Estrogen receptor α; Side chain; Cell line; Uterus; Antagonist; Chemical synthesis; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.07.072

The synthesis and biological evaluation of two series of conformationally restricted SERMs are disclosed. In each series (benzothiophene or naphthalene), the ligand side chain is constrained to adopt a defined orientation. The orientation of the side chain has a significant impact on functional activity. For selective estrogen receptor modulators (SERMs), the orientation of the basic side chain relative to the SERM core has a significant impact on function. The synthesis and biological evaluation of two series of SERMs are disclosed, where the ligand side chain is constrained to adopt a defined orientation. Compounds where the side chain is forced into the plane of the SERM core have a different profile compared to those compounds where the side chain is pseudo-orthogonal, particularly with regard to antagonism of estradiol action on an Ishikawa uterine cell line.