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

doi:10.1021/jm061035y

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

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	399-403
Number of pages	5
Journal	Journal of Medicinal Chemistry
Volume	50
Issue number	2
DOIs	https://doi.org/10.1021/jm061035y
State	Published - Jan 25 2007

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/jm061035y

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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

Zhou, HB, Sheng, S, Compton, DR, Kim, Y, Joachimiak, A, Sharma, S, Carlson, KE, Katzenellenbogen, BS, Nettles, KW, Greene, GL & Katzenellenbogen, JA 2007, 'Structure-guided optimization of estrogen receptor binding affinity and antagonist potency of pyrazolopyrimidines with basic side chains', Journal of Medicinal Chemistry, vol. 50, no. 2, pp. 399-403. https://doi.org/10.1021/jm061035y

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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.",

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

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doi = "10.1021/jm061035y",

language = "English (US)",

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T1 - Structure-guided optimization of estrogen receptor binding affinity and antagonist potency of pyrazolopyrimidines with basic side chains

AU - Zhou, Hai Bing

AU - Sheng, Shubin

AU - Compton, Dennis R.

AU - Kim, Younchang

AU - Joachimiak, Andrzej

AU - Sharma, Sanjay

AU - Carlson, Kathryn E.

AU - Katzenellenbogen, Benita S.

AU - Nettles, Kendall W.

AU - Greene, Geoffrey L.

AU - Katzenellenbogen, John A.

PY - 2007/1/25

Y1 - 2007/1/25

N2 - 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.

AB - 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.

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

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