Identification of new triarylethylene oxyalkanoic acid analogues as bone selective estrogen mimetics.
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 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-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 17 beta-estradiol in suppressing serum markers of bone resorption/turnover, namely osteocalcin and deoxypyridinoline, but had only 30% of the uterotrophic efficacy of 17 beta-estradiol. This study has thus identified two triarylethylene oxybutyric acids, 6 and 7, that have differential bone/uterus effects like those of known SERMs.
Rubin
V N
VN
College of Pharmacy, University of Georgia, Athens, GA 30602-2352, USA.
Ruenitz
P C
PC
Boudinot
F D
FD
Boyd
J L
JL
D000596:Amino Acids / Q000097:blood; D000818:Animals; D001711:Biotransformation; D001862:Bone Resorption / Q000188:drug therapy; D002087:Butyrates / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D018716:Molecular Mimicry; D009929:Organ Size / Q000187:drug effects; D015675:Osteocalcin / Q000097:blood / Q000187:drug effects; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry* / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects
C435821:4-(1-(des-hydroxyphenyl)-2-phenyl-1-butenyl)phenoxy-n-butanoic acid; C435822:4-(1-(p-hydroxyphenyl)-2-phenyl-1-butenyl)phenoxy-n-butanoic acid; D000596:Amino Acids; D002087:Butyrates; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D015675:Osteocalcin; C036020:deoxypyridinoline