Stephen Cho

Evaluation of the major metabolites of raloxifene as modulators of tissue selectivity

Raloxifene (LY139481 HCl) is a selective estrogen receptor modulator (SERM) which blocks the effects of estrogen on some tissues, such as the breast and uterus, while mimicking estrogen in other tissues, such as bone. To study the origins of this unique pharmacology, we have prepared the major metabolites of raloxifene as chemical probes for examining the estrogen receptor function in vitro and in vivo. In human breast cancer cell (MCF-7) related assays, these glucuronide conjugates show little affinity for the estrogen receptor and are more than two orders of magnitude less potent at inhibiting cell proliferation than raloxifene. In non-traditional estrogen target tissue, such as bone, these metabolites are less effective than the parent at inhibiting cytokine-stimulated bone resorbing activity in rat osteoclasts or producing transforming growth factor beta-3 (TGF-beta3). In animal models, tissue distribution studies with radiolabelled metabolite indicate that conversion to raloxifene occurs readily in a variety of tissues including the liver, lung, spleen, kidney, bone and uterus. Differential conversion of metabolite in target organs, such as bone and the uterus, is not observed indicating that the origin of raloxifenes pharmacology does not result from tissue-selective deconjugation of metabolite to parent.

Synthesis and estrogen receptor binding affinities of the major human metabolites of raloxifene (LY139481)

Glucuronide conjugates 1 and 2, the major metabolites of raloxifene, have been prepared and their molecular interactions with the estrogen receptor determined.

Synthesis and pharmacology of 2-alkyl raloxifene analogs

Abstract A series of 2-alkyl and 2-cycloalkyl raloxifene analogs have been prepared and evaluated in both in vitro and in vivo models of estrogen/antiestrogen activity. In particular, the 2-cyclohexyl analogs show promise as potent selective estrogen-receptor modulators (SERMs).