Pyrazolo[1,5-α]pyrimidines: Estrogen receptor ligands possessing estrogen receptor β antagonist activity

Dennis R. Compton, Shubin Sheng, Kathryn E. Carlson, Natalie A. Rebacz, In Young Lee, Benita S. Katzenellenbogen, John A. Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

In our search for novel subtype-selective estrogen receptor (ER) ligands, we have examined various heterocyclic units as core structural elements. Here, we have investigated the fused, bicyclic pyrazolo[1,5-a]pyrimidine core, which is a system that allows for analogues to be readily assembled in a library-like fashion. This series of pyrazolo[1,5-a]pyrimidine ER ligands provided us with a new pharmacological profile for an ER ligand: compounds that are passive on both ERs, with a distinct potency selectivity in favor of ERβ. The most distinctive ligand in this series, 2-phenyl-3-(4-hydroxyphenyl)-5,7- bis(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine, was 36-fold selective for ERβ in binding. Curiously, on the basis of molecular modeling, the ERβ binding selectivity of compounds in this series appears to be derived from differing orientations that they adapt in the ligand binding pockets of ERα vs ERβ. In transcription assays this pyrazolopyrimidine was fully effective as an ERβ antagonist while exhibiting no significant activity on ERα. Thus, this ligand functions as a potency- and efficacy-selective ERβ antagonist that would abrogate estrogen action through ERβ with minimal effects on its activity through ERα; as such, it could be used to study the biological function of ERβ.

Original languageEnglish (US)
Pages (from-to)5872-5893
Number of pages22
JournalJournal of Medicinal Chemistry
Volume47
Issue number24
DOIs
StatePublished - Nov 18 2004

Fingerprint

Pyrimidines
Estrogen Receptors
Ligands
Estrogen Receptor Antagonists
Libraries
Estrogens

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Pyrazolo[1,5-α]pyrimidines : Estrogen receptor ligands possessing estrogen receptor β antagonist activity. / Compton, Dennis R.; Sheng, Shubin; Carlson, Kathryn E.; Rebacz, Natalie A.; Lee, In Young; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.

In: Journal of Medicinal Chemistry, Vol. 47, No. 24, 18.11.2004, p. 5872-5893.

Research output: Contribution to journalArticle

Compton, Dennis R. ; Sheng, Shubin ; Carlson, Kathryn E. ; Rebacz, Natalie A. ; Lee, In Young ; Katzenellenbogen, Benita S. ; Katzenellenbogen, John A. / Pyrazolo[1,5-α]pyrimidines : Estrogen receptor ligands possessing estrogen receptor β antagonist activity. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 24. pp. 5872-5893.
@article{768a23bf5f51497cb227efbede4192bb,
title = "Pyrazolo[1,5-α]pyrimidines: Estrogen receptor ligands possessing estrogen receptor β antagonist activity",
abstract = "In our search for novel subtype-selective estrogen receptor (ER) ligands, we have examined various heterocyclic units as core structural elements. Here, we have investigated the fused, bicyclic pyrazolo[1,5-a]pyrimidine core, which is a system that allows for analogues to be readily assembled in a library-like fashion. This series of pyrazolo[1,5-a]pyrimidine ER ligands provided us with a new pharmacological profile for an ER ligand: compounds that are passive on both ERs, with a distinct potency selectivity in favor of ERβ. The most distinctive ligand in this series, 2-phenyl-3-(4-hydroxyphenyl)-5,7- bis(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine, was 36-fold selective for ERβ in binding. Curiously, on the basis of molecular modeling, the ERβ binding selectivity of compounds in this series appears to be derived from differing orientations that they adapt in the ligand binding pockets of ERα vs ERβ. In transcription assays this pyrazolopyrimidine was fully effective as an ERβ antagonist while exhibiting no significant activity on ERα. Thus, this ligand functions as a potency- and efficacy-selective ERβ antagonist that would abrogate estrogen action through ERβ with minimal effects on its activity through ERα; as such, it could be used to study the biological function of ERβ.",
author = "Compton, {Dennis R.} and Shubin Sheng and Carlson, {Kathryn E.} and Rebacz, {Natalie A.} and Lee, {In Young} and Katzenellenbogen, {Benita S.} and Katzenellenbogen, {John A.}",
year = "2004",
month = "11",
day = "18",
doi = "10.1021/jm049631k",
language = "English (US)",
volume = "47",
pages = "5872--5893",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "24",

}

TY - JOUR

T1 - Pyrazolo[1,5-α]pyrimidines

T2 - Estrogen receptor ligands possessing estrogen receptor β antagonist activity

AU - Compton, Dennis R.

AU - Sheng, Shubin

AU - Carlson, Kathryn E.

AU - Rebacz, Natalie A.

AU - Lee, In Young

AU - Katzenellenbogen, Benita S.

AU - Katzenellenbogen, John A.

PY - 2004/11/18

Y1 - 2004/11/18

N2 - In our search for novel subtype-selective estrogen receptor (ER) ligands, we have examined various heterocyclic units as core structural elements. Here, we have investigated the fused, bicyclic pyrazolo[1,5-a]pyrimidine core, which is a system that allows for analogues to be readily assembled in a library-like fashion. This series of pyrazolo[1,5-a]pyrimidine ER ligands provided us with a new pharmacological profile for an ER ligand: compounds that are passive on both ERs, with a distinct potency selectivity in favor of ERβ. The most distinctive ligand in this series, 2-phenyl-3-(4-hydroxyphenyl)-5,7- bis(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine, was 36-fold selective for ERβ in binding. Curiously, on the basis of molecular modeling, the ERβ binding selectivity of compounds in this series appears to be derived from differing orientations that they adapt in the ligand binding pockets of ERα vs ERβ. In transcription assays this pyrazolopyrimidine was fully effective as an ERβ antagonist while exhibiting no significant activity on ERα. Thus, this ligand functions as a potency- and efficacy-selective ERβ antagonist that would abrogate estrogen action through ERβ with minimal effects on its activity through ERα; as such, it could be used to study the biological function of ERβ.

AB - In our search for novel subtype-selective estrogen receptor (ER) ligands, we have examined various heterocyclic units as core structural elements. Here, we have investigated the fused, bicyclic pyrazolo[1,5-a]pyrimidine core, which is a system that allows for analogues to be readily assembled in a library-like fashion. This series of pyrazolo[1,5-a]pyrimidine ER ligands provided us with a new pharmacological profile for an ER ligand: compounds that are passive on both ERs, with a distinct potency selectivity in favor of ERβ. The most distinctive ligand in this series, 2-phenyl-3-(4-hydroxyphenyl)-5,7- bis(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine, was 36-fold selective for ERβ in binding. Curiously, on the basis of molecular modeling, the ERβ binding selectivity of compounds in this series appears to be derived from differing orientations that they adapt in the ligand binding pockets of ERα vs ERβ. In transcription assays this pyrazolopyrimidine was fully effective as an ERβ antagonist while exhibiting no significant activity on ERα. Thus, this ligand functions as a potency- and efficacy-selective ERβ antagonist that would abrogate estrogen action through ERβ with minimal effects on its activity through ERα; as such, it could be used to study the biological function of ERβ.

UR - http://www.scopus.com/inward/record.url?scp=8644228523&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=8644228523&partnerID=8YFLogxK

U2 - 10.1021/jm049631k

DO - 10.1021/jm049631k

M3 - Article

C2 - 15537344

AN - SCOPUS:8644228523

VL - 47

SP - 5872

EP - 5893

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 24

ER -