Design, synthesis, and biological evaluation of new raloxifene analogues of improved antagonist activity and endometrial safety.

Raloxifene agonism of estrogen receptor (ER) in post-menopausal endometrium is not negligible. Based on a rational drug design workflow, we synthesized 14 analogues of raloxifene bearing a polar group in the aromatic ring of the basic side chain (BSC) and/or changes in the bulkiness of the BSC amino group. Analogues with a polar BSC aromatic ring and amino group substituents of increasing volume displayed increasing ER antagonism in Ishikawa cells. Analogues with cyclohexylaminoethoxy (13a) or adamantylaminoethoxy BSC (13b) lacking a polar aromatic ring displayed high ER-binding affinity and ER antagonism in Ishikawa cells higher than raloxifene and similar to fulvestrant (ICI182,780). The endometrial surface epithelium of immature female CD1 mice injected with 13b was comparable to that of vehicle-treated mice, while that of mice treated with estradiol, raloxifene or 13b in combination with estradiol was hyperplastic. These findings indicate that raloxifene analogues with a bulky BSC amino group could provide for higher endometrial safety treatment of the menopausal syndrome.