Recently, we developed a novel triaryl-substituted pyrazole ligand system that has high affinity for the estrogen receptor (ER) (Fink, B. E.: Mortenson, D. S.: Stauffer, S. R.; Aron, Z. D.: Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205). Subsequent work has shown that some analogues in this series are very selective for the ERalpha subtype in terms of binding affinity and agonist potency (Stauffer, S. R.: Coletta, C. J.: Tedesco. R.: Sun, J.: Katzenellenbogen, J. A. J. Med. Chem. 2000, submitted). We now investigate how this pyrazole ER agonist system might be converted into an antagonist or a selective estrogen receptor modifier (SERM) by incorporating a basic or polar side chain like those typically found in antiestrogens and known to be essential determinants of their mixed agonist/antagonist character. We selected an N-piperidinyl-ethyl chain as a first attempt, and introduced it at the four possible sites of substitution on the pyrazole core structure to determine the orientation that the pyrazole might adopt in the ER ligand binding pocket. Of these four, the C(5) piperidinyl-ethoxy-substituted pyrazole 5 had by far the highest affinity. Also, it bound to the ER subtype alpha (ERalpha) with 20-fold higher affinity than to ERbeta. In cell-based transcription assays, pyrazole 5 was an antagonist on both ERalpha and ERbeta, and it was also more potent on ERalpha. Based on structure-binding affinity relationships and on molecular modeling studies of these pyrazoles in a crystal structure of the ERalpha-raloxifene complex, we propose that pyrazoles having a basic substituent on the C(5) phenyl group adopt a binding mode that is different from that of the pyrazole agonists that lack this group. The most favorable orientation appears to be one which places the N(1) phenol in the A-ring binding pocket so that the basic side chain can adopt an orientation similar to that of the basic side chain of raloxifene.