The estrogen receptor (ER) ligand 4-[1-(p-hydroxyphenyl)-2-phenylethyl]phenoxyacetic acid (HPPA) was previously found to have differential bone loss suppressive effects in the ovariectomized (OVX) rat approaching those of selective ER modulators (SERMs) like tamoxifen. In an effort to improve efficacy and bioavailability, analogs of this compound were prepared which incorporated features designed to reduce polarity/ionizability. Thus, the acetic acid side chain of HPPA was replaced by n-butanoic acid and 1H-tetrazol-4-ylmethyl moieties, to give 11 and 12, respectively. Also, the phenolic hydroxyl of HPPA was replaced, giving deoxy analog 13. In addition, new methods for the synthesis of triarylethylene variants 11, namely 4-{[1- (p-hydroxyphenyl)-2-phenyl-1-butenyl]phenoxy}-n-butanoic acid (10) and its deshydroxy counterpart (9) were developed. The former of these was previously shown to have in vitro antiestrogenic effects characteristic of known SERMs. | In the OVX, 9 and 10 were as effective as 17-estradiol (E2) in suppressing serum markers of bone turnover, namely osteocalcin and deoxypyridinoline, but had only 30% the uterotrophic efficacy of E2. Furthermore, 9 and 10 each lowered serum cholesterol levels by about 30% with respect to vehicle treated controls, and were able to suppress body weight gain to a degree approaching that of E2. | This study has therefore identified two triarylethylene oxybutyric acids, 9 and 10, that display differential estrogenicity similar to that seen with establishes SERMs.