There is a medical need for an agent with the positive effects of estrogen on bone and the cardiovascular system, but without the negative effects on reproductive tissue. Raloxifene (LY139481 HCI) is a benzothiophene derivative that binds to the estrogen receptor and inhibits the effects of estrogen on the uterus. In an ovariectomized (OVX) rat model we investigated the effects of raloxifene on bone loss (induced by estrogen deficiency), serum lipids, and uterine tissue. After oral administration of raloxifene for 5 wk (0.1-10 mg/kg per d) to OVX rats, bone mineral density in the distal femur and proximal tibia was significantly greater than that observed in OVX controls (ED50 of 0.03-0.3 mg/kg). Serum cholesterol was lower in the raloxifene-treated animals, which had a minimal effective dose of 0.1 mg/kg and an approximate oral ED50 of 0.2 mg/kg. The effects of raloxifene on bone and serum cholesterol were comparable to those of a 0.1-mg/kg per d oral dose of ethynyl estradiol. Raloxifene diverged dramatically from estrogen in its lack of significant estrogenic effects on uterine tissue. Ethynyl estradiol produced a marked elevation in a number of uterine histologic parameters (e.g., epithelial cell height, stromal eosinophilia). These data suggest that raloxifene has promise as an agent with beneficial bone and cardiovascular effects in the absence of significant uterine effects. (J. Clin. Invest. 1994. 93:63-69.)

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In an effort to prepare nonsteroidal antiestrogens demonstrating greater antagonism and less intrinsic estrogenicity than those currently available, a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives was synthesized. These compounds were prepared by Friedel-Crafts aroylation of appropriate O-protected 2-arylbenzo[b]thiophene nuclei with basic side-chain-bearing benzoyl chlorides followed by removal of the protective groups to provide the desired compounds containing both hydroxyl and basic side-chain functionality. A particularly useful method for the cleavage of aryl methoxy ethers without removal of (dialkylamino)ethoxy side chain functionality elsewhere in the molecule was found to be AlCl3/EtSH. The benzothiophene derivatives were tested for their ability to inhibit the growth-stimulating action of estradiol on the immature rat uterus. Seemingly minor changes in the side-chain amine moiety were found to have profound effects on the ability of the compounds to antagonize estradiol. Analogues having basic side chains containing cyclic (pyrrolidine, piperidine, and hexamethyleneamine) moieties were found to have less intrinsic estrogenicity and to antagonize estradiol action more completely than their noncyclic counterparts. The most effective antiestrogen in the series, compound 44, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b] thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone, elicited a modest uterotropic activity that did not increase with increasing dose. In antagonism of estradiol, 44 exhibited a degree of inhibition surpassing that of tamoxifen at any dose tested. The new benzothiophene antiestrogen was also shown to have high affinity for rat uterine cycloplasmic estrogen receptor and to be an inhibitor of the growth of DMBA-induced rat mammary tumors.

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