SYNTHESIS AND PHARMACOLOGY OF CONFORMATIONALLY RESTRICTED RALOXIFENE ANALOGS - HIGHLY POTENT SELECTIVE ESTROGEN-RECEPTOR MODULATORS

The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen recept or modulator (SERM) which is currently under clinical evaluation for t he prevention and treatment of postmenopausal osteoporosis. In vivo st ructure-activity relationships and molecular modeling studies have ind icated that the orientation of the basic amine-containing side chain o f 1, relative to the stilbene plane, is an important discriminating fa ctor for the maintenance of tissue selectivity. We have constructed a series of analogues of 1 in which this side chain is held in an orient ation which is orthogonal to the stilbene plane, similar to the low-en ergy conformation predicted for raloxifene. Herein, we report on the s ynthesis of these compounds and on their activity in a series of in vi tro and in vivo biological assays reflective of the SERM profile. In p articular, we describe their ability to (I) bind the estrogen receptor , (2) antagonize estrogen-stimulated proliferation of MCF-7 cells in v itro, (3) stimulate TGF-beta 3 gene expression in cell culture, (4) in hibit the uterine effects of ethynyl estradiol in immature rats, and ( 5) potently reduce serum cholesterol and protect against osteopenia in ovariectomized (OVX) rats without estrogen-like stimulation of uterin e tissue. These data demonstrate that one of these compounds, LY357489 , 4, is among the most potent SERMs described to date with in vivo eff icacy on bone and cholesterol metabolism in OVX rats at doses as low a s 0.01 mg/kg/d.