Solid-phase synthesis of tetrasubstituted pyrazoles, novel ligands for the estrogen receptor

Shaun R. Stauffer, John A. Katzenellenbogen

Research output: Contribution to journalArticlepeer-review


Most ligands for the estrogen receptor (ER) are not well suited for synthesis by combinatorial means, because their construction involves a series of carbon - carbon bond forming reactions that are not uniformly high yielding. In previous work directed to overcoming this limitation, we surveyed various phenol-substituted five-membered heterocycles, hoping to find a system that would afford both high ER binding affinity and whose synthesis could be adapted to solid-phase methods (Fink et al. Chem. Biol. 1999, 6, 206-219.) In this report, we have developed a reliable and efficient solid-phase method to prepare the best of these heterocycles, the tetrasubstituted pyrazoles, and we have used this methodology to produce small, discrete libraries of these novel ER ligands. We used a combination of FT-IR and nanoprobe 1H NMR-MAS to characterize intermediates leading up to the final pyrazole products directly on the bead. We also developed a scavenging resin, which enabled us to obtain products free from inorganic contaminants. We prepared a 12-member test library, and then a 96-member library, and in both cases we determined product purity and ER binding affinity of all of the library members. Several interesting binding affinity patterns have emerged from these studies, and they have provided us with new directions for further exploration, which has led to pyrazoles having high affinity and potency as agonists and antagonists toward the ERa subtype.

Original languageEnglish (US)
Pages (from-to)318-329
Number of pages12
JournalJournal of Combinatorial Chemistry
Issue number4
StatePublished - 2000

ASJC Scopus subject areas

  • Chemistry(all)


Dive into the research topics of 'Solid-phase synthesis of tetrasubstituted pyrazoles, novel ligands for the estrogen receptor'. Together they form a unique fingerprint.

Cite this