Pyrazole ligands: Structure - Affinity/activity relationships and estrogen receptor-α-selective agonists

S. R. Stauffer, C. J. Coletta, R. Tedesco, G. Nishiguchi, K. Carlson, J. Sun, B. S. Katzenellenbogen, J. A. Katzenellenbogen

Research output: Contribution to journalArticle


We have found that certain tetrasubstituted pyrazoles are high-affinity ligands for the estrogen receptor (ER) (Fink et al. Chem. Biol. 1999, 6, 205-219) and that one pyrazole is considerably more potent as an agonist on the ERα than on the ERβ subtype (Sun et al. Endocrinology 1999, 140, 800-804). To investigate what substituent pattern provides optimal ER binding affinity and the greatest enhancement of potency as an ERα-selective agonist, we prepared a number of tetrasubstituted pyrazole analogues with defined variations at certain substituent positions. Analysis of their binding affinity pattern shows that a C(4)-propyl substituent is optimal and that a p-hydroxyl group on the N(1)-phenyl group also enhances affinity and selectivity for ERα. The best compound in this series, a propylpyrazole triol (PPT, compound 4g), binds to ERα with high affinity (ca. 50% that of estradiol), and it has a 410-fold binding affinity preference for ERα. It also activates gene transcription only through ERα. Thus, this compound represents the first ERα-specific agonist. We investigated the molecular basis for the exceptional ERα binding affinity and potency selectivity of pyrazole 4g by a further study of structure-affinity relationships in this series and by molecular modeling. These investigations suggest that the pyrazole triols prefer to bind to ERα with their C(3)-phenol in the estradiol A-ring binding pocket and that binding selectivity results from differences in the interaction of the pyrazole core and C(4)-propyl group with portions of the receptor where ERα has a smaller residue than ERβ. These ER subtype-specific interactions and the ER subtype-selective ligands that can be derived from them should prove useful in defining those biological activities in estrogen target cells that can be selectively activated through ERα.

Original languageEnglish (US)
Pages (from-to)4934-4947
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number26
StatePublished - Dec 28 2000

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Stauffer, S. R., Coletta, C. J., Tedesco, R., Nishiguchi, G., Carlson, K., Sun, J., Katzenellenbogen, B. S., & Katzenellenbogen, J. A. (2000). Pyrazole ligands: Structure - Affinity/activity relationships and estrogen receptor-α-selective agonists. Journal of Medicinal Chemistry, 43(26), 4934-4947.