Triarylpyrazoles with basic side chains: Development of pyrazole-based estrogen receptor antagonists

Recently, we developed a novel triaryl-substituted pyrazole ligand system t hat has high affinity for the estrogen receptor (ER) (Fink, B. E.; Mortenso n, 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 serie s are very selective for the ERT alpha. subtype in terms of binding affinit y and agonist potency (Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Sun, J .; Katzenellenbogen, J. A. J. Med. Chem. 2000, submitted). We now investiga te how this pyrazole ER agonist system might be converted into an antagonis t 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. W e selected an N-piperidinyl-ethyl chain as a first attempt, and introduced it at the four possible sites of substitution on the pyrazole core structur e to determine the orientation that the pyrazole might adopt in the ER liga nd binding pocket. Of these four, the C(5) piperidinyl-ethoxy-substituted p yrazole 5 had by far the highest affinity. Also, it bound to the ER subtype alpha (ER alpha) with 20-fold higher affinity than to ERP. In cell-based t ranscription assays, pyrazole 5 was an antagonist on both ER alpha and ER b eta, and it was also more potent on ER alpha. Based on structure-binding af finity relationships and on molecular modeling studies of these pyrazoles i n a crystal structure of the ER alpha -raloxifene complex, we propose that pyrazoles having a basic substituent on the C(5) phenyl group adopt a bindi ng 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 ad opt an orientation similar to that of the basic side chain of raloxifene. ( CV) 2000 Elsevier Science Ltd. All rights reserved.