Structure-activity relationships of selective estrogen receptor modulators: modifications to the 2-arylbenzothiophene core of raloxifene.
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.
Grese
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TA
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Cho
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S
Finley
D R
DR
Godfrey
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AG
Jones
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Lugar
C W
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Martin
M J
MJ
Matsumoto
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Pennington
L D
LD
Winter
M A
MA
Adrian
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Cole
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Magee
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Phillips
D L
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Rowley
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Short
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Glasebrook
A L
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Bryant
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D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D001665:Binding Sites; D001842:Bone and Bones / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D020849:Raloxifene Hydrochloride; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects / Q000201:enzymology
D004965:Estrogen Antagonists; D010880:Piperidines; D011960:Receptors, Estrogen; D020849:Raloxifene Hydrochloride; D002784:Cholesterol