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Pipendoxifene is a new 2-Ph indole SERM that exhibits an excellent preclin. pharmacol. profile and was selected for further development as a treatment for metastatic breast cancer.

Tamoxifen is an antiestrogen used in women who have estrogen receptor (ER)-.alpha.-pos. breast cancer. Unfortunately, resistance to tamoxifen is common in women with metastatic disease and side effects, including increased risk of endometrial cancer, exist. Greenberger et al's research showed that In preclin. models, ERA-923 has an improved efficacy and safety compared with tamoxifen.  The ability of ERA-923, 4-OH tamoxifen, or raloxifene to inhibit estrogen-stimulated growth was evaluated in cell-based and xenograft assays with tumor cells that are sensitive or resistant to tamoxifen. Uterine effects of selective ER modulators were compared in rodents. ERA-923 potently inhibits estrogen binding to ER-.alpha. (IC50, 14 nM). In ER-.alpha.-pos. human MCF-7 breast carcinoma cells, ERA-923 inhibits estrogen-stimulated growth (IC50, 0.2 nM) assocd. with cytostasis. In vitro, a MCF-7 variant with inherent resistance to tamoxifen (10-fold) or 4-OH tamoxifen (> 1000-fold) retains complete sensitivity to ERA-923. Partial sensitivity to ERA-923 exists in MCF-7 variants that have acquired profound tamoxifen resistance. In tumor-bearing animals, ERA-923 (10 mg/kg/day given p.o.) inhibits 17.beta.-estradiol-stimulated growth in human tumors derived from MCF-7, EnCa-101 endometrial, or BG-1 ovarian carcinoma cells, including a MCF-7-variant that is inherently resistant to tamoxifen. Raloxifene is inactive in the MCF-7 xenograft model. Unlike tamoxifen, droloxifene, or raloxifene, ERA-923 is not uterotropic in immature rats or ovariectomized mice. Consistent with this, tamoxifen, but not ERA-923, stimulates the growth of EnCa-101 tumors. see Clinical Cancer Research (2001), 7(10), 3166-3177.

Current developer:    Wyeth Pharmaceuticals (Originator), Ligand (Codevelopment)

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