Structure-guided optimization of estrogen receptor binding affinity and antagonist potency of pyrazolopyrimidines with basic side chains.
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.
Zhou
Hai-Bing
HB
Department of Chemistry, University of Illinois, Urbana, Illinois 61801, USA.
Sheng
Shubin
S
Compton
Dennis R
DR
Kim
Younchang
Y
Joachimiak
Andrzej
A
Sharma
Sanjay
S
Carlson
Kathryn E
KE
Katzenellenbogen
Benita S
BS
Nettles
Kendall W
KW
Greene
Geoffrey L
GL
Katzenellenbogen
John A
JA
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
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D011720:Pyrazoles; D011743:Pyrimidines