title: Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists.
abstract: 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 ERalpha than on the ERbeta 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 ERalpha-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 ERalpha. The best compound in this series, a propylpyrazole triol (PPT, compound 4g), binds to ERalpha with high affinity (ca. 50% that of estradiol), and it has a 410-fold binding affinity preference for ERalpha. It also activates gene transcription only through ERalpha. Thus, this compound represents the first ERalpha-specific agonist. We investigated the molecular basis for the exceptional ERalpha 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 ERalpha 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 ERalpha has a smaller residue than ERbeta. 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 ERalpha.
authors.affiliation: Department of Chemistry, University of Illinois and University of Illinois College of Medicine, Urbana, Illinois 61801, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Stauffer
authors.forename: C J
authors.initials: CJ
authors.lastname: Coletta
authors.forename: R
authors.initials: R
authors.lastname: Tedesco
authors.forename: G
authors.initials: G
authors.lastname: Nishiguchi
authors.forename: K
authors.initials: K
authors.lastname: Carlson
authors.forename: J
authors.initials: J
authors.lastname: Sun
authors.forename: B S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.forename: J A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D001667:Binding, Competitive; D047628:Estrogen Receptor alpha; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D011960:Receptors, Estrogen / Q000819:agonists*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D047628:Estrogen Receptor alpha; D008024:Ligands; D010636:Phenols; D011720:Pyrazoles; D011960:Receptors, Estrogen; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol