Osteoporosis is a severely debilitating skeletal disease in postmenopausal women. Estrogen replacement therapy (ERT) offers benefits like preventing bone loss and reducing cardiovascular risk but is associated with side effects including uterine bleeding, fluid retention, and increased risks of endometrial and breast cancer, leading to poor compliance. Raloxifene, a nonsteroidal estrogen receptor modulator, has limited oral bioavailability due to extensive glucuronidation, compromising in vivo potency. To address these issues, we sought a novel nonsteroidal estrogen receptor agonist/antagonist with good oral bioavailability, retaining estrogen's beneficial effects on bone and the cardiovascular system while avoiding adverse side effects. We synthesized a series of tetrahydronaphthalene derivatives, leveraging nonplanar topology to minimize intestinal glucuronidation based on structure-activity relationship (SAR) studies of glucuronosyltransferases. Screening included estrogen receptor binding affinity, pharmacokinetic analysis, and in vivo evaluations (ovariectomized (OVX) rat model for bone mineral density, serum cholesterol, and uterine effects; MCF-7 breast cancer cells for antiproliferative activity). The levorotatory enantiomer 14 (CP-336156) exhibited high oral bioavailability (62% in rat, 45% in monkey), potent estrogen receptor binding (IC50 11.3 nM), prevented OVX-induced bone loss (ED50 < 1 µg/kg/day) and lowered serum cholesterol (ED50 10 µg/kg/day) without causing uterine hypertrophy. It also potently inhibited the proliferation of estrogen-sensitive MCF-7 cells (IC50 0.05 nM). CP-336156 is a novel diaryltetrahydronaphthalene with excellent oral bioavailability, tissue-selective estrogenic activity, and is currently undergoing clinical evaluation in postmenopausal women.