174264-47-2Relevant articles and documents
LYMPH DIRECTING PRODRUGS
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Page/Page column 47; 48, (2016/02/29)
H:\dar\Interwoven\NRPortbl\DCC\DAR\8230712_1.doc-12/08/2015 Abstract The present invention relates to compounds and their uses, in particular, compounds in the form of prodrugs that promote transport of a pharmaceutical agent to the lymphatic system and subsequently enhance release of the parent drug.
Structure-activity relationships of selective estrogen receptor modulators: Modifications to the 2-arylbenzothiophene core of raloxifene
Grese, Timothy A.,Cho, Stephen,Finley, Don R.,Godfrey, Alexander G.,Jones, Charles D.,Lugar III, Charles W.,Martin, Michael J.,Matsumoto, Ken,Pennington, Lewis D.,Winter, Mark A.,Adrian, M. Dee,Cole, Harlan W.,Magee, David E.,Phillips, D. Lynn,Rowley, Ellen R.,Short, Lorri L.,Glasebrook, Andrew L.,Bryant, Henry U.
, p. 146 - 167 (2007/10/03)
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.
