Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
2
|
| pubmed:dateCreated |
1997-2-21
|
| pubmed:abstractText |
The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. A series of raloxifene analogs which contain modifications to the 2-arylbenzothiophene core have been prepared and evaluated for the ability to bind to the estrogen receptor and inhibit MCF-7 breast cancer cell proliferation in vitro. Their ability to function as tissue-selective estrogen agonists in vivo has been assayed in a short-term, ovariectomized (OVX) rat model with end points of serum cholesterol lowering, uterine weight gain, and uterine eosinophil peroxidase activity. These studies have demonstrated that (1) the 6-hydroxy and, to a lesser extent, the 4'-hydroxy substituents of raloxifene are important for receptor binding and in vitro activity, (2) small, highly electronegative 4'-substituents such as hydroxy, fluoro, and chloro are preferred both in vitro and in vivo, (3) increased steric bulk at the 4'-position leads to increased uterine stimulation in vivo, and (4) additional substitution of the 2-aryl moiety is tolerated while additional substitution at the 4-, 5-, or 7-position of the benzothiophene results in reduced biological activity. In addition, compounds in which the 2-aryl group is replaced by alkyl, cycloalkyl, and naphthyl substituents maintain a profile of in vitro and in vivo biological activity qualitatively similar to that of raloxifene. Several novel structural variants including 2-cyclohexyl, 2-naphthyl, and 6-carbomethoxy analogs also demonstrated efficacy in preventing bone loss in a chronic OVX rat model of postmenopausal osteopenia, at doses of 0.1-10 mg/kg.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cholesterol,
http://linkedlifedata.com/resource/pubmed/chemical/Estrogen Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Piperidines,
http://linkedlifedata.com/resource/pubmed/chemical/Raloxifene,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Estrogen
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Jan
|
| pubmed:issn |
0022-2623
|
| pubmed:author |
pubmed-author:AdrianM DMD,
pubmed-author:BryantH UHU,
pubmed-author:ChoSS,
pubmed-author:ColeH WHW,
pubmed-author:FinleyD RDR,
pubmed-author:GlasebrookA LAL,
pubmed-author:GodfreyA GAG,
pubmed-author:GreseT ATA,
pubmed-author:JonesC DCD,
pubmed-author:LugarC WCW3rd,
pubmed-author:MageeD EDE,
pubmed-author:MartinM JMJ,
pubmed-author:MatsumotoKK,
pubmed-author:PenningtonL DLD,
pubmed-author:PhillipsD LDL,
pubmed-author:RowleyE RER,
pubmed-author:ShortL LLL,
pubmed-author:WinterM AMA
|
| pubmed:issnType |
Print
|
| pubmed:day |
17
|
| pubmed:volume |
40
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
146-67
|
| pubmed:dateRevised |
2004-11-17
|
| pubmed:meshHeading |
pubmed-meshheading:9003514-Adenocarcinoma,
pubmed-meshheading:9003514-Animals,
pubmed-meshheading:9003514-Binding Sites,
pubmed-meshheading:9003514-Bone and Bones,
pubmed-meshheading:9003514-Breast Neoplasms,
pubmed-meshheading:9003514-Cell Division,
pubmed-meshheading:9003514-Cholesterol,
pubmed-meshheading:9003514-Estrogen Antagonists,
pubmed-meshheading:9003514-Female,
pubmed-meshheading:9003514-Humans,
pubmed-meshheading:9003514-Male,
pubmed-meshheading:9003514-Organ Size,
pubmed-meshheading:9003514-Ovariectomy,
pubmed-meshheading:9003514-Piperidines,
pubmed-meshheading:9003514-Raloxifene,
pubmed-meshheading:9003514-Rats,
pubmed-meshheading:9003514-Rats, Sprague-Dawley,
pubmed-meshheading:9003514-Receptors, Estrogen,
pubmed-meshheading:9003514-Structure-Activity Relationship,
pubmed-meshheading:9003514-Uterus
|
| pubmed:year |
1997
|
| pubmed:articleTitle |
Structure-activity relationships of selective estrogen receptor modulators: modifications to the 2-arylbenzothiophene core of raloxifene.
|
| pubmed:affiliation |
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
|
| pubmed:publicationType |
Journal Article
|