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

Previously, the estrogen receptor (ER) ligand 4-[1-(p-hydroxyphenyl)-2-phen ylethyl]phenoxyacetic acid (5) was found to have differential bone loss sup pressive effects in the ovariectomized (OVX) rat approaching those of selec tive ER modulators (SERMs) such as tamoxifen. In an effort to improve effic acy, analogues of this compound were prepared which incorporated features d esigned to reduce polarity/ionizability. Thus, the acetic acid side chain o f 5 was replaced by n-butanoic acid and 1H-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-p henyl- 1-butenyl]phenoxy)-n-butanoic acid (6) and its des-hydroxy counterpa rt (7), because the former of these had in vitro antiestrogenic effects cha racteristic of known SERMs. In the OVX rat, 6 and 7 were as effective as 17 beta -estradiol in suppressing serum markers of bone resorption/turnover, namely osteocalcin and deoxypyridinoline, but had only 30% of the uterotrop hic efficacy of 17 beta -estradiol. This study has thus identified two tria rylethylene oxybutyric acids, 6 and 7, that have differential bone/uterus e ffects like those of known SERMs. (C) 2001 Elsevier Science Ltd. All rights reserved.