title: Structure-guided optimization of estrogen receptor binding affinity and antagonist potency of pyrazolopyrimidines with basic side chains.
abstract: 2,3-Diarylpyrazolo[1,5-a]pyrimidines are estrogen receptor (ER) antagonists of modest potency that we have described previously. Guided by the crystal structure of an ER-ligand complex that we have obtained with one of these compounds, we prepared analogs that contain a basic side chain at the 2- or 3-aryl group and quickly found one that, according to the structure-based prediction, shows an increase in binding affinity and antagonist potency and a loss of residual agonist activity.
authors.affiliation: Department of Chemistry, University of Illinois, Urbana, Illinois 61801, USA.
authors.forename: Hai-Bing
authors.initials: HB
authors.lastname: Zhou
authors.forename: Shubin
authors.initials: S
authors.lastname: Sheng
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Compton
authors.forename: Younchang
authors.initials: Y
authors.lastname: Kim
authors.forename: Andrzej
authors.initials: A
authors.lastname: Joachimiak
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sharma
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.forename: Kendall W
authors.initials: KW
authors.lastname: Nettles
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Greene
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D011720:Pyrazoles; D011743:Pyrimidines