Identification of new triarylethylene oxyalkanoic acid analogues as bone selective estrogen mimetics

• Published in: Bioorganic & medicinal chemistry 2001-06, Vol.9 (6), p.1579-1587
• Main Authors: Rubin, Valeria N, Ruenitz, Peter C, Boudinot, F.Douglas, Boyd, Jason L
• Format: Article
• Language: English
• Subjects: Amino Acids - blood; Animals; Biological and medical sciences; Biotransformation; Bone Resorption - drug therapy; Bones, joints and connective tissue. Antiinflammatory agents; Butyrates - chemistry; Butyrates - pharmacology; Drug Design; Drug Evaluation, Preclinical; Female; Hormones. Endocrine system; Medical sciences; Molecular Mimicry; Organ Size - drug effects; Osteocalcin - blood; Osteocalcin - drug effects; Ovariectomy; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptors, Estrogen - metabolism; Selective Estrogen Receptor Modulators - chemistry; Selective Estrogen Receptor Modulators - pharmacology; Tamoxifen - pharmacology; Uterus - anatomy & histology; Uterus - drug effects
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(01)00038-4

Previously, the estrogen receptor (ER) ligand 4-[1-( p-hydroxyphenyl)-2-phenylethyl]phenoxyacetic acid ( 5) was found to have differential bone loss suppressive effects in the ovariectomized (OVX) rat approaching those of selective ER modulators (SERMs) such as tamoxifen. In an effort to improve efficacy, analogues of this compound were prepared which incorporated features designed to reduce polarity/ionizability. Thus, the acetic acid side chain of 5 was replaced by n-butanoic acid and 1 H-tetrazol-4-ylmethyl moieties, to give 8 and 10, respectively. Also, the phenolic hydroxyl of 5 was replaced, giving deoxy analogue 9. We also developed new methods for the synthesis of triarylethylene variants of 5 and 9, namely 4-{[1-( p-hydroxyphenyl)-2-phenyl-1-butenyl]phenoxy}- n-butanoic acid ( 6) and its des-hydroxy counterpart ( 7), because the former of these had in vitro antiestrogenic effects characteristic of known SERMs. In the OVX rat, 6 and 7 were as effective as 17β-estradiol in suppressing serum markers of bone resorption/turnover, namely osteocalcin and deoxypyridinoline, but had only 30% of the uterotrophic efficacy of 17β-estradiol. This study has thus identified two triarylethylene oxybutyric acids, 6 and 7, that have differential bone/uterus effects like those of known SERMs. Oxybutyric acids 6 and 7 have been found to have an activity profile similar to estabished selective estrogen receptor modulators (SERMs) with significant bone protecting effects and minimal uterotrophic activity