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dc.contributor.authorRubin, Valeria Norma
dc.date.accessioned2014-03-03T20:02:12Z
dc.date.available2014-03-03T20:02:12Z
dc.date.issued2001-08
dc.identifier.otherrubin_valeria_n_200108_phd
dc.identifier.urihttp://purl.galileo.usg.edu/uga_etd/rubin_valeria_n_200108_phd
dc.identifier.urihttp://hdl.handle.net/10724/20248
dc.description.abstractThe 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<E2>-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.
dc.publisheruga
dc.rightspublic
dc.subjecttamoxifen
dc.subjectSERMs
dc.subjectosteoporosis
dc.subjectraloxifene
dc.subjectestrogen replacement therapy
dc.titleTamoxifen analogs bearing acidic-side chain substituents
dc.title.alternativesynthesis and biological evaluation
dc.typeDissertation
dc.description.degreePhD
dc.description.departmentPharmaceutical and Biomedical Sciences
dc.description.majorPharmacy (Medicinial Chemistry)
dc.description.advisorPeter C. Ruenitz
dc.description.committeePeter C. Ruenitz
dc.description.committeeMichael Bartlett
dc.description.committeeWarren Beach
dc.description.committeeAnthony Cappomacchia
dc.description.committeeRandall Tackett


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