DISCOVERY AND SYNTHESIS OF OXY]PHENOXY]-2-(4-HYDROXYPHENYL)]BENZO[B]THIOPHENE - A NOVEL, HIGHLY POTENT, SELECTIVE ESTROGEN-RECEPTOR MODULATOR

3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone hydrochloride (2), is representative of a class of compounds known as selective estrogen receptor modulators (SERMs) that possess estrogen agonist-like actions on bone tissues and serum lipids while displaying potent estrogen ant agonist properties in the breast and uterus. As part of ongoing SAR st udies with raloxifene, we found that replacement of the carbonyl group with oxygen oxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydroc hloride, 4c) resulted in a substantial (10-fold) increase in estrogen antagonist potency relative to raloxifene in an in vitro estrogen depe ndent cell proliferation assay (IC50 = 0.05 nM) in which human breast cancer cells (MCF-7) were utilized. In vivo, 4c potently inhibited the uterine proliferative response to exogenous estrogen in immature rats following both sc and oral dosing (ED50 of 0.006 and 0.25 mg/kg, resp ectively). In ovariectomized aged rats, 4c produced a significant maxi mal decrease (45%) in total cholesterol at 1.0 mg/kg (po) and showed a protective effect on bone relative to controls with maximal efficacy at 1.0 mg/kg (po). These data identify 4c as a novel SERM with greater potency to antagonize estrogen in uterine tissue and in human mammary cancer cells compared to raloxifene, tamoxifen or ICI-182,780.