Table.

Current status of new SERMs

Drug Name	Category (Structure)	Effects	Preclinical Results	Clinical Status
Toremifene	Tamoxifen-like	Breast cancer treatment	Fewer genotoxic effects than tamoxifen [113], bone effects similar to tamoxifen [119]	FDA approved for metastatic breast cancer
		Heart protection		Phase II trial (65 women) better than tamoxifen regulating lipid metabolism [121, 122]
		Mastalgia treatment		Phase II trials (62 and 195 women) effective [126, 127]
		Prostate cancer prevention		Phase II trial (514 men) decreases prostate cancer incidence [128]
		Relieve side effects of androgen deprivation therapy		Phase III trial (1,389 men) improves lipid profiles [130]
				Phase III trial (1,392 men) increases bone mineral density [129]
Ospemifene	Tamoxifen-like	Vaginal atrophy treatment	Estrogenic effects on vaginal epithelium that is not observed with tamoxifen or raloxifene [134–136]	Phase III trial (826 women) relieves vaginal dryness
		Osteoporosis treatment		Phase II trial (118 women): Comparable to or slightly better than raloxifene [139]
				Phase III trial planned (detail not available)
		Breast cancer prevention	Inhibits tumor growth in animal models as effective as tamoxifen [140, 141]	Not available
GW5638 (DPC974) & GW7604	Tamoxifen-like	Breast cancer treatment (2nd line therapy)	Works as a SERM and as a SERD [148], effective in tamoxifen-resistant tumors [144, 145]; functions as an ER agonist in bone and cardiovascular system but an antagonist in breast and endometrium [142]	Phase I trial (9 patients who failed first-line hormone therapy) low toxicity [ASCO meeting 2002, abstract 452]
Arzoxifene (LY353381)	Raloxifene-like	Breast cancer treatment	Antiestrogenic in breast and endometrium, estrogenic in bone and lipids [150]	Phase III trial (200 patients) inferior to tamoxifen [154]
		Breast cancer prevention	Effective to prevent ER-positive and ER-negative mammary tumors especially in combination with LG100268 [140, 155]	Phase I trials (50 and 76 women) low toxicity and favorable biomarker profile [156]
Lasofoxifene (CP-336156, Fablyn)	Raloxifene-like	Osteoporosis treatment and prevention	Higher potency than tamoxifen and raloxifene [158]; higher oral bioavailability than raloxifene [160]	Phase III trial (1,907 women) significantly increases bone mineral density compared to placebo, no endometrial effects, no association with thromboembolic disorder [159]
				Phase III trial to compare with raloxifene (CORAL trial, details not available)
		Vaginal atrophy treatment		Phase III trail (445 patients) improves vaginal atrophy compared to placebo
		Breast cancer treatment and prevention	Effects similar to tamoxifen to prevent and treat NMU-induced mammary tumor in rats [163]	Phase III trial (PEARL trial with 8,556 women), reduces ER-positive breast cancer incidence compared to placebo; slightly decreases major coronary disease risk; reduces vertebral and non-vertebral fractures; increases risks of venous thromboembolic events but not stroke; no endometrial effects [SABCS 2008, abstract 11]
		Heart disease prevention
Pipendoxifene (ERA-923)	Raloxifene-like	Breast cancer treatment	Inhibits tamoxifen-sensitive and -resistant tumors in mice and rats no uterotrophic activities compared to raloxifene [167]	Phase II trial to treat tamoxifen-refractory breast cancer in postmenopausal women (details not available)
Bazedoxifene (TSE-424 WAY-140424)	Raloxifene-like	Osteoporosis treatment and prevention	Increases bone density with little uterine or vasomotor effects	Phase III trial (7,492 women) reduces vertebral and non-vertebral fracture incidences, while raloxifene is not effective against non-vertebral fracture [171]
				Phase III trial (497 women) reduces endometrial thickness, unique property among known SERMs [170]
		Breast cancer prevention	Inhibits estrogen-stimulated breast cancer cells growth [169]	Not available
Acolbifene (EM-652, SCH57068) & EM-800 (SCH57050)	Raloxifene-like	Breast cancer treatment (2nd line therapy)	Highest affinity for ER, inhibit growth of multiple breast cancer cells in vitro and in vivo [180]	Phase III trial, less effective than anastrozole to treat tamoxifen-resistance breast cancer, study halted [182]
		Breast cancer treatment (1st line therapy)		Phase III trial planned [182]
		Breast cancer prevention		Phase II trial (started in February, 2009) for premenopausal women
CHF4227	Raloxifene-like	Breast cancer and osteoporosis prevention	Prevents DMBA-induced mammary tumors and preserves bone mass in rats [184, 185];	Phase I trials (24 and 56 women) beneficial on bone markers and lipid metabolism; no effects on endometrium; not causing hot flashes
SP500263	Raloxifene-like	Breast cancer and osteoporosis treatment	Inhibits breast cancer cell growth in vitro and in vivo without stimulating uterine weight gain [188, 189], protects bone in vitro [190]	Not available
HMR3339	Steroidal	Osteoporosis and cardiovascular disease prevention	Better than raloxifene to protect cancellous bones [191]	Phase II trials (96 and 118 and 94 women) better than raloxifene at improving some beneficial cardiovascular markers [192–194]
PSK3471	Steroidal	Osteoporosis and breast cancer prevention and treatment	Prevents bone loss in vivo, inhibits growth of breast cancer cells in vivo [197]	Not available
Trilostane (Modrenal)	ER subtype-selective	Breast cancer treatment	Increases estradiol binding to ERβ, increases ERβ expression, partially inhibits estrogen production [214, 215]	Approved in UK to treat advanced postmenopausal breast cancer after relapse to initial hormone therapy
				Phase III trial (714 women with advanced breast cancer) effective for both ER-positive and ER-negative breast cancer, effective for endocrine therapy-resistant cancer
				Phase II trial for use in premenopausal breast cancer (details not available)
		Prostate cancer treatment		Phase II trial with hormone-refractory prostate cancer (details not available)
TAS-108 (SR16234)	Steroidal, ER subtype-selective	Breast cancer treatment and prevention	Inhibits growth of tamoxifen- and AI-sensitive and resistant cancer cells in vitro and in vivo; inhibits DMBA-induced tumor growth in rats [216]	Phase I trials (16 and 15 women) effective and well tolerated [218, 219]
				Phase II trails (145 and 97 postmenopausal women with advanced breast cancer) beneficial effects, well tolerated [SABCS, 2008, abstract 2131 and 2132]