Structure-guided optimization of estrogen receptor binding affinity and antagonist potency of pyrazolopyrimidines with basic side chains

Hai Bing Zhou, Shubin Sheng, Dennis R. Compton, Younchang Kim, Andrzej Joachimiak, Sanjay Sharma, Kathryn E. Carlson, Benita S. Katzenellenbogen, Kendall W. Nettles, Geoffrey L. Greene, John A. Katzenellenbogen

Abstract

2,3-Diarylpyrazolo[1,5-α]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.

Original languageEnglish (US)
Pages (from-to)399-403
Number of pages5
JournalJournal of Medicinal Chemistry
Volume50
Issue number2
DOIs
StatePublished - Jan 25 2007

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Zhou, H. B., Sheng, S., Compton, D. R., Kim, Y., Joachimiak, A., Sharma, S., Carlson, K. E., Katzenellenbogen, B. S., Nettles, K. W., Greene, G. L., & Katzenellenbogen, J. A. (2007). Structure-guided optimization of estrogen receptor binding affinity and antagonist potency of pyrazolopyrimidines with basic side chains. Journal of Medicinal Chemistry, 50(2), 399-403. https://doi.org/10.1021/jm061035y