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7.07.5.1.4.2 Triphenylethylenes with antagonist side chains

The group of Katzenellenbogen has attempted to convert pyrazole-based estrogen receptor agonists such as 27 (Figure 14), into antagonists by appending a piperidinyl-ethyl side chain found in many SERMs such as raloxifene.76 Four pyrazole derivatives were prepared with the basic side chain capping each phenol sequentially or appended to the pyrazole C4 position via an alkyl chain. Of the compounds tested, the C5-piperidinyl-ethoxy-substituted pyrazole (28) displayed the highest affinity for both ERa (RBA = 11.5%) and ERb (RBA = 0.65%) (purified recombinant estrogen receptor) and was ~ 18-fold selective for ERa. Not surprisingly, the addition of the basic side chain had a significant effect on transcriptional activity. The compound showed no stimulation of transcription in transfected HEC-1 cells, and was found to be a full antagonist on ERa (IC50 b20 nmol L"1) and ERb (IC50 b -160nmolL 1). The selectivity in the transfection assay parallels the binding selectivity, in that 28 displays ERa-selectivity in both assays. Molecular modeling studies based on the x-ray crystal structure of raloxifene bound to ERa suggested that the N1 phenol occupies the E2 A-ring binding pocket, and that the C4-ethyl occupies a subpocket normally occupied by the 18-methyl of E2. This binding mode contrasts with that predicted for pyrazoles such as PPT (Figure 9), which lack the basic side chain where the C3-phenol acts as the estrogen A-ring mimic.

In a similar effort to convert triaryl furan estrogen receptor agonists into antagonists, a series of compounds containing the ethoxypiperidine side chain has been examined.77 Furan (29) (Figure 15), was shown to have the highest affinity and was almost 25-fold selective for ERa (RBA ERa = 75%; RBA ERb = 3.1%, recombinant human, full-length estrogen receptor). Derivatives lacking the phenolic OH group at various positions indicated that compound 29

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