SP500263, a novel SERM, blocks osteoclastogenesis in a human bone cell model: role of IL-6 and GM-CSF.

Bone metabolism requires tightly coupled activities exhibited by two unique cell populations, the bone-resorbing osteoclasts and the bone-forming osteoblasts. Imbalance in the function of these two cell types can result in osteoporosis, a condition characterized by loss in bone integrity and of bone mass. We developed a human bone cell culture model that allows the in vitro study of bone formation and osteoclastogenesis and employed this bone model for the screening and pharmacological analyses of protein and small molecule therapeutics.

Structure-activity relationship studies of ethyl 2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate: an inhibitor of AP-1 and NF-kappaB mediated gene expression.

Several analogues of ethyl 2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate (1) were synthesized and tested as inhibitors of AP-1 and NF-kappaB mediated transcriptional activation in Jurkat T cells. From our SAR work, ethyl 2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))-N-methylamino]-4-(trifluoromethyl)-pyrimidine-5-carboxylate was identified as a novel and potent inhibitor.

Effects of SP500263, a novel, potent antiestrogen, on breast cancer cells and in xenograft models.

We have compared the antitumor activities of SP500263, a novel next-generation selective estrogen receptor modulator (SERM), tamoxifen, and raloxifene side-by-side in in vitro and in vivo MCF-7 breast cancer models. In vitro, SP500263 acted as an antiestrogen and potently inhibited estrogen-dependent MCF-7 proliferation with IC(50) values in the nanomolar range. SP500263 also strongly inhibited MCF-7 proliferation in the absence of estrogen at all of the concentrations tested.

Differential response of estrogen receptors alpha and beta to SP500263, a novel potent selective estrogen receptor modulator.

We determined the differential response of a novel SERM, SP500263, on estrogen receptor (ER) alpha and the more recently cloned ER-beta. Because of the high homology of amino acid residues in the ligand-binding domain of ER-alpha and ER-beta, we were not surprised to find that SP500263 binds to both ERs equally well. In contrast, SP500263 acts as a strong estrogen agonist in a strictly ER-alpha-specific manner in U2OS osteosarcoma cell lines blocking the production of interleukin (IL) 6 and granulocyte macrophage colony-stimulating factor.