Differential estrogen receptor subtype modulators: assessment of estrogen receptor subtype-binding selectivity and transcription-regulating properties of new cycloalkyl pyrazoles.

ABSTRACT

Several new cycloalkyl-fused diaryl pyrazoles were synthesized and their binding affinity for the estrogen receptor (ER) subtypes, ERalpha and ERbeta, and subtype-specific agonist/antagonist properties were determined. Cyclopentane- and cyclohexane-fused pyrazoles with p-hydroxyphenyl rings at positions 1 and 3 displayed modest ERbeta-binding selectivity and variable agonism through ERalpha, while behaving as full estrogen antagonists through ERbeta in estrogen-responsive element (ERE)-dependent gene expression assays. By contrast, the 2,3-diphenolic derivatives were non-selective and considerably less effective ERbeta antagonists compared to 1,3-diphenolic ones. The cyclohexane-fused 1,3-diphenolic pyrazole 8, in particular, behaved as full ERalpha agonist/ERbeta antagonist in these assays. Molecular modelling revealed the structural determinants possibly accounting for the differential regulation of transcription through the two ERs exhibited by 8. The data also shows that the ER subtype-binding selectivity and agonist/antagonist efficacy of the 1,3-diphenolic pyrazoles is influenced by the cycloalkyl ring fused to the pyrazole core. Using 8 we show that, though the mutant androgen receptor (AR) of LNCaP cells is required for estrogen as well as androgen stimulation of cell growth, estrogen responsiveness of the cells depends on ERbeta and AR but not on ERalpha.