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

Most ligands for the estrogen receptor (ER) are not well suited for synthes is 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 variou s phenol-substituted five-membered heterocycles, hoping to find a system th at 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 meth od to prepare the best of these heterocycles, the tetrasubstituted pyrazole s, and we have used this methodology to produce small, discrete libraries o f these novel ER ligands. We used a combination of FT-IR and nanoprobe H-1 NMR-MAS to characterize intermediates leading up to the final pyrazole prod ucts directly on the bead. We also developed a scavenging resin, which enab led us to obtain products free from inorganic contaminants. We prepared a 1 2-member test library, and then a 96-member library, and in both cases we d etermined product purity and ER binding affinity of all of the library memb ers. Several interesting binding affinity patterns have emerged from these studies, and they have provided us with new directions for further explorat ion, which has led to pyrazoles having high affinity and potency as agonist s and antagonists toward the ER alpha subtype.