Raloxifene was discovered in the late 1970s as part of Lilly's quest to find an oestrogen-modulating compound that did not have side effects on the uterus. Indeed, raloxifene is a selective oestrogen receptor modulator (SERM) that either inhibits or stimulates oestrogen-mediated actions in a tissue-specific manner, depending on the extent of co-activator and co-repressor recruitment to oestrogen receptor target gene promoters. It acts as an oestrogen agonist in bone, decreasing bone resorption and bone turnover, whereas it acts as an oestrogen antagonist in uterine and breast tissues.
During Phase I studies in the early 1980s, the compound was found to have low bioavailability, because it was rapidly metabolized to form inactive glucuronide conjugates. Despite problems associated with bioavailability, Lilly proceeded to a clinical trial of raloxifene in patients with breast cancer — although it was found to have no antitumour activity in this condition — and further tested raloxifene in animal models of bone loss. Following positive results in bone loss models, clinical trials began in 1992 and Lilly filed three patents (US 6,906,086, US RE39,049 and US RE38,968; collectively known as the 'bone loss patents'). Evista was approved by the US Food and Drug Administration (FDA) for the treatment of osteoporosis in 1997 (and for reducing the risk of invasive breast cancer in 2007).
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