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Owen Brendan Wallace - One of the best experts on this subject based on the ideXlab platform.
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A selective Estrogen receptor modulator for the treatment of hot flushes.
Journal of Medicinal Chemistry, 2006Co-Authors: Owen Brendan Wallace, Kenneth S. Lauwers, Jeffrey Alan Dodge, Joel R. Calvin, Ronald Jay Hinklin, Mary D. Adrian, Henry Uhlman Bryant, Pamela K. Shetler, Andrew G GeiserAbstract:A selective Estrogen receptor modulator (SERM) for the potential treatment of hot flushes is described. (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, LSN2120310, potently binds ERalpha and ERbeta and is an Antagonist in MCF-7 breast adenocarcinoma and Ishikawa uterine cancer cell lines. The compound is a potent Estrogen Antagonist in the rat uterus. In ovariectomized rats, the compound lowers cholesterol, maintains bone mineral density, and is efficacious in a morphine dependent rat model of hot flush efficacy.
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A New Selective Estrogen Receptor Modulator with Potent Uterine Antagonist Activity, Agonist Activity in Bone, and Minimal Ovarian Stimulation
Endocrinology, 2005Co-Authors: Andrew G Geiser, Mary D. Adrian, Michael W. Draper, Conrad Wilson Hummel, Judith W. Henck, Ilene R. Cohen, Daniel G. Rudmann, Kevin B. Donnelly, Timothy Alan Shepherd, Owen Brendan WallaceAbstract:The use of selective Estrogen receptor modulators for the treatment of Estrogen-dependent diseases in premenopausal women has been hindered by undesirable ovarian stimulation and associated risks of ovarian cysts. We have identified a selective Estrogen receptor modulator compound (LY2066948) that is a strong Estrogen Antagonist in the uterus yet has minimal effects on the ovaries of rats. LY2066948 binds with high affinity to both Estrogen receptors and has potent Estrogen Antagonist activity in human uterine and breast cancer cells. Oral administration of LY2066948 to immature rats blocked uterine weight gain induced by ethynyl estradiol with an ED50 of 0.07 mg/kg. Studies in mature rats demonstrated that LY2066948 decreases uterine weight by 51% after 35 d treatment, confirming potent uterine Antagonist activity over several estrous cycles. This strong uterine response contrasted with the minimal effects on the ovaries: serum estradiol levels remained within the normal range, whereas histologic evaluat...
Andrew G Geiser - One of the best experts on this subject based on the ideXlab platform.
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A selective Estrogen receptor modulator for the treatment of hot flushes.
Journal of Medicinal Chemistry, 2006Co-Authors: Owen Brendan Wallace, Kenneth S. Lauwers, Jeffrey Alan Dodge, Joel R. Calvin, Ronald Jay Hinklin, Mary D. Adrian, Henry Uhlman Bryant, Pamela K. Shetler, Andrew G GeiserAbstract:A selective Estrogen receptor modulator (SERM) for the potential treatment of hot flushes is described. (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, LSN2120310, potently binds ERalpha and ERbeta and is an Antagonist in MCF-7 breast adenocarcinoma and Ishikawa uterine cancer cell lines. The compound is a potent Estrogen Antagonist in the rat uterus. In ovariectomized rats, the compound lowers cholesterol, maintains bone mineral density, and is efficacious in a morphine dependent rat model of hot flush efficacy.
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A New Selective Estrogen Receptor Modulator with Potent Uterine Antagonist Activity, Agonist Activity in Bone, and Minimal Ovarian Stimulation
Endocrinology, 2005Co-Authors: Andrew G Geiser, Mary D. Adrian, Michael W. Draper, Conrad Wilson Hummel, Judith W. Henck, Ilene R. Cohen, Daniel G. Rudmann, Kevin B. Donnelly, Timothy Alan Shepherd, Owen Brendan WallaceAbstract:The use of selective Estrogen receptor modulators for the treatment of Estrogen-dependent diseases in premenopausal women has been hindered by undesirable ovarian stimulation and associated risks of ovarian cysts. We have identified a selective Estrogen receptor modulator compound (LY2066948) that is a strong Estrogen Antagonist in the uterus yet has minimal effects on the ovaries of rats. LY2066948 binds with high affinity to both Estrogen receptors and has potent Estrogen Antagonist activity in human uterine and breast cancer cells. Oral administration of LY2066948 to immature rats blocked uterine weight gain induced by ethynyl estradiol with an ED50 of 0.07 mg/kg. Studies in mature rats demonstrated that LY2066948 decreases uterine weight by 51% after 35 d treatment, confirming potent uterine Antagonist activity over several estrous cycles. This strong uterine response contrasted with the minimal effects on the ovaries: serum estradiol levels remained within the normal range, whereas histologic evaluat...
Michael W. Draper - One of the best experts on this subject based on the ideXlab platform.
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A New Selective Estrogen Receptor Modulator with Potent Uterine Antagonist Activity, Agonist Activity in Bone, and Minimal Ovarian Stimulation
Endocrinology, 2005Co-Authors: Andrew G Geiser, Mary D. Adrian, Michael W. Draper, Conrad Wilson Hummel, Judith W. Henck, Ilene R. Cohen, Daniel G. Rudmann, Kevin B. Donnelly, Timothy Alan Shepherd, Owen Brendan WallaceAbstract:The use of selective Estrogen receptor modulators for the treatment of Estrogen-dependent diseases in premenopausal women has been hindered by undesirable ovarian stimulation and associated risks of ovarian cysts. We have identified a selective Estrogen receptor modulator compound (LY2066948) that is a strong Estrogen Antagonist in the uterus yet has minimal effects on the ovaries of rats. LY2066948 binds with high affinity to both Estrogen receptors and has potent Estrogen Antagonist activity in human uterine and breast cancer cells. Oral administration of LY2066948 to immature rats blocked uterine weight gain induced by ethynyl estradiol with an ED50 of 0.07 mg/kg. Studies in mature rats demonstrated that LY2066948 decreases uterine weight by 51% after 35 d treatment, confirming potent uterine Antagonist activity over several estrous cycles. This strong uterine response contrasted with the minimal effects on the ovaries: serum estradiol levels remained within the normal range, whereas histologic evaluat...
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Selective Estrogen Receptor Modulators and Postmenopausal Women's Health
Journal of Womens Health, 1997Co-Authors: Henry Uhlman Bryant, Michael W. DraperAbstract:ABSTRACT Selective Estrogen receptor modulators represent an alternative approach to the use of Estrogen replacement therapy or hormone replacement therapy for decreasing postmenopausal bone loss, as well as for reducing the incidence of serious cardiovascular disease in this population. Of particular interest is raloxifene, a benzothiophene compound, which binds with high affinity to the Estrogen receptor and produces effects similar to Estrogen on the skeleton and cardiovascular system but behaves as a complete Estrogen Antagonist in the uterus and the breast. The pharmacologic profile of raloxifene, a discussion of a possible mechanism of action, and the potential role of this drug in women's postmenopausal health are the subjects of this review.
David D. Thompson - One of the best experts on this subject based on the ideXlab platform.
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droloxifene a new Estrogen Antagonist agonist prevents bone loss in ovariectomized rats
Endocrinology, 1995Co-Authors: Hua Zhu Ke, Hollis A. Simmons, Christine M. Pirie, D. Todd Crawford, David D. ThompsonAbstract:The purpose of this study was to determine the effects of droloxifene (DRO), a new Estrogen Antagonist/agonist, on bone turnover, bone mass, total serum cholesterol, and uterine weight in rats made Estrogen deficient by ovariectomy. Sprague-Dawley female rats were ovariectomized (OVX) or sham operated (sham) at 5 months of age and treated with 17 beta-estradiol (E2) at 30 micrograms/kg, sc, daily or with DRO at 5, 10, or 20 mg/kg.day, orally, for 4 weeks. At the time of death, body weight gain, uterine weight, and total serum cholesterol were measured. Bone area, bone mineral content (BMC), and bone mineral density (BMD) of whole femora, distal femoral metaphyses, femoral shaft, and proximal femora were determined ex vivo using dual energy x-ray absorptiometry. Static and dynamic cancellous bone histomorphometric analysis of proximal tibial metaphyses was performed in double fluorescent labeled, undecalcified, 4- and 10-microns longitudinal sections. Body weight gain in E2-treated OVX rats was significant...
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Droloxifene, a new Estrogen Antagonist/agonist, prevents bone loss in ovariectomized rats.
Endocrinology, 1995Co-Authors: Hua Zhu Ke, Hollis A. Simmons, Christine M. Pirie, D. Todd Crawford, David D. ThompsonAbstract:The purpose of this study was to determine the effects of droloxifene (DRO), a new Estrogen Antagonist/agonist, on bone turnover, bone mass, total serum cholesterol, and uterine weight in rats made Estrogen deficient by ovariectomy. Sprague-Dawley female rats were ovariectomized (OVX) or sham operated (sham) at 5 months of age and treated with 17 beta-estradiol (E2) at 30 micrograms/kg, sc, daily or with DRO at 5, 10, or 20 mg/kg.day, orally, for 4 weeks. At the time of death, body weight gain, uterine weight, and total serum cholesterol were measured. Bone area, bone mineral content (BMC), and bone mineral density (BMD) of whole femora, distal femoral metaphyses, femoral shaft, and proximal femora were determined ex vivo using dual energy x-ray absorptiometry. Static and dynamic cancellous bone histomorphometric analysis of proximal tibial metaphyses was performed in double fluorescent labeled, undecalcified, 4- and 10-microns longitudinal sections. Body weight gain in E2-treated OVX rats was significant...
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droloxifene a new Estrogen Antagonist agonist prevents bone loss in ovariectomized rats
Endocrinology, 1995Co-Authors: Hua Zhu Ke, Hollis A. Simmons, Christine M. Pirie, D. Todd Crawford, David D. ThompsonAbstract:The purpose of this study was to determine the effects of droloxifene (DRO), a new Estrogen Antagonist/agonist, on bone turnover, bone mass, total serum cholesterol, and uterine weight in rats made Estrogen deficient by ovariectomy. Sprague-Dawley female rats were ovariectomized (OVX) or sham operated (sham) at 5 months of age and treated with 17 beta-estradiol (E2) at 30 micrograms/kg, sc, daily or with DRO at 5, 10, or 20 mg/kg.day, orally, for 4 weeks. At the time of death, body weight gain, uterine weight, and total serum cholesterol were measured. Bone area, bone mineral content (BMC), and bone mineral density (BMD) of whole femora, distal femoral metaphyses, femoral shaft, and proximal femora were determined ex vivo using dual energy x-ray absorptiometry. Static and dynamic cancellous bone histomorphometric analysis of proximal tibial metaphyses was performed in double fluorescent labeled, undecalcified, 4- and 10-microns longitudinal sections. Body weight gain in E2-treated OVX rats was significant...
Henry Uhlman Bryant - One of the best experts on this subject based on the ideXlab platform.
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A selective Estrogen receptor modulator for the treatment of hot flushes.
Journal of Medicinal Chemistry, 2006Co-Authors: Owen Brendan Wallace, Kenneth S. Lauwers, Jeffrey Alan Dodge, Joel R. Calvin, Ronald Jay Hinklin, Mary D. Adrian, Henry Uhlman Bryant, Pamela K. Shetler, Andrew G GeiserAbstract:A selective Estrogen receptor modulator (SERM) for the potential treatment of hot flushes is described. (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, LSN2120310, potently binds ERalpha and ERbeta and is an Antagonist in MCF-7 breast adenocarcinoma and Ishikawa uterine cancer cell lines. The compound is a potent Estrogen Antagonist in the rat uterus. In ovariectomized rats, the compound lowers cholesterol, maintains bone mineral density, and is efficacious in a morphine dependent rat model of hot flush efficacy.
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Selective Estrogen Receptor Modulators: An Alternative to Hormone Replacement Therapy
Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York N.Y.), 1998Co-Authors: Henry Uhlman Bryant, Willard H. DereAbstract:Estrogen is a key regulatory hormone, which in addition to its role in reproduction, affects a number of physiological systems, including the skeleton and cardiovascular system. The important role of Estrogen in various tissues is perhaps most evident in postmenopausal women who, in addition to menopausal symptoms, experience increases in osteoporosis and coronary heart disease as their Estrogen levels decline. Estrogen replacement, while effective against osteoporosis and heart disease, produces a number of side effects associated with the breast and uterus which limits compliance. Selective Estrogen receptor modulators (SERMs), such as raloxifene and tamoxifen, produce beneficial Estrogen-like effects on bone and lipid metabolism, while antagonizing Estrogen in reproductive tissue. SERMs can be distinguished from each other in reproductive tissue, particularly the uterus, by their activity profile. For example, while triphenylethylenes like tamoxifen behave as partial agonists, raloxifene (a benzothiophene) behaves as a complete Antagonist in the uterus. The SERM profile is distinct from that of full Estrogens (ie. 17beta-estradiol or 17alpha-dihydroequilenin) which behave as Estrogen agonists in all tissues and pure Estrogen Antagonists (i.e. ICI-164,384) which exhibit only an Estrogen Antagonist profile in a battery of tissue types. The precise mechanism by which SERMs produce this tissue-selective pharmacology remains a question. It is clear, however, that for raloxifene, both the Estrogen agonist effects on bone and cholesterol metabolism as well as the Estrogen Antagonist effects in uterine and mammary tissue involve high affinity interaction with the Estrogen receptor. The Estrogen Antagonist activity is mediated via classical pharmacological competition for Estrogen receptor binding. The Estrogen agonist activity, in bone for example, appears to involve novel post-receptor pathways and non-classical Estrogen response element(s) which are activated by SERMs. These novel response elements may represent natural pathways which respond to Estrogen metabolites in vivo.
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Selective Estrogen Receptor Modulators and Postmenopausal Women's Health
Journal of Womens Health, 1997Co-Authors: Henry Uhlman Bryant, Michael W. DraperAbstract:ABSTRACT Selective Estrogen receptor modulators represent an alternative approach to the use of Estrogen replacement therapy or hormone replacement therapy for decreasing postmenopausal bone loss, as well as for reducing the incidence of serious cardiovascular disease in this population. Of particular interest is raloxifene, a benzothiophene compound, which binds with high affinity to the Estrogen receptor and produces effects similar to Estrogen on the skeleton and cardiovascular system but behaves as a complete Estrogen Antagonist in the uterus and the breast. The pharmacologic profile of raloxifene, a discussion of a possible mechanism of action, and the potential role of this drug in women's postmenopausal health are the subjects of this review.