Structure–activity relationships and sub-type selectivity in an oxabicyclic estrogen receptor α/β agonist scaffold

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 5; pp. 1463 - 1466
• Main Authors: Hamann, Lawrence G., Meyer, J. Hoyt, Ruppar, Daniel A., Marschke, Keith B., Lopez, Francisco J., Allegretto, Elizabeth A., Karanewsky, Donald S.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.2005; Elsevier
• Subjects: Administration, Oral; Alkenes - chemistry; Alkenes - pharmacology; Animals; Biological and medical sciences; Bridged Bicyclo Compounds - chemistry; Bridged Bicyclo Compounds - pharmacology; Dose-Response Relationship, Drug; Estrogen receptor; Estrogen Receptor alpha - agonists; Estrogen Receptor alpha - physiology; Estrogen Receptor beta - agonists; Estrogen Receptor beta - physiology; Female; Hormones. Endocrine system; Medical sciences; Models, Animal; Molecular Conformation; Organ Size - drug effects; Osteoporosis; Ovariectomy; Pharmacology. Drug treatments; Phenols - chemistry; Rats; Stereoisomerism; Structure-Activity Relationship; Uterus - cytology; Uterus - drug effects; Estrogen receptor; Osteoporosis; Agonist; Rat; Rodentia; Benzene derivatives; Oral administration; Selectivity; Oxygen heterocycle; In vitro; Primary alcohol; Estrogen receptor β; In vivo; Estrogen receptor α; Vertebrata; Mammalia; Structure activity relation; Uterus; Animal; Bicyclic compound; Chemical synthesis; Non steroid compound; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.12.077

The synthesis and estrogen receptor α/β agonist activity of compounds from this novel scaffold are reported. An oxabicyclic template for estrogen receptor α and β agonists has been identified which can be tuned to provide moderate levels of selectivity for either receptor sub-type. Structure–activity relationships within this phenol-substituted oxabicyclo[3.3.1]nonene series are described. Select compounds from the present series showed activity in vivo after oral dosing in rodent models of uterine proliferation.