Selective estrogen receptor modulators - A look ahead

Selective estrogen receptor modulators (SERMs) are structurally diverse com pounds that bind to estrogen receptors (ER) and elicit agonist or antagonis t responses depending on the target tissue and hormonal milieu. They are be ing evaluated primarily for conditions associated with aging, including hor mone-responsive cancer, osteoporosis and cardiovascular disease. Several SE RMs are marketed or are in clinical development, including triphenylethylen es (tamoxifen and its derivatives: toremifene, droloxifene and idoxifene), chromans (levormeloxifene), benzothiophenes (raloxifene, LY353381) and naph thalenes (CP336,156). Tamoxifen and toremifene, both used to treat advanced breast cancer, also have beneficial effects on bone mineral density and se rum lipids in postmenopausal women. Tamoxifen was recently shown to decreas e the risk of invasive breast cancer in women at high risk. Unfortunately, both drugs also have stimulatory effects on the endometrium. Raloxifene, us ed for prevention of postmenopausal osteoporosis and fragility fractures, a lso has favourable effects on bone mineral density, serum lipids and the in cidence of invasive breast cancer in postmenopausal women but does not stim ulate the endometrium. Like replacement estrogens, SERMs increase the risk of venous thromboembolism. SERMs offer postmenopausal women many of the adv antages of estrogen replacement while mitigating some of the disadvantages, particularly the concern over breast cancer. Newer SERMs, exemplified by r aloxifene, also eliminate the concerns over endometrial stimulation that we re not addressed by first generation SERMs. The clinical success of SERMs h as set the stage for a variety of drug therapies based on selective modulat ion of nuclear receptor activity.