Estrogen receptor ligands. Part 10

Chromanes: Old scaffolds for new SERAMs

Qiang Tan, Timothy A. Blizzard, Jerry D. Morgan, Elizabeth T. Birzin, Wanda Chan, Yi Tien Yang, Lee Yuh Pai, Edward C. Hayes, Carolyn A. Dasilva, Sudha Warrier, Joel Yudkovitz, Hilary A. Wilkinson, Nandini Sharma, Paula M.D. Fitzgerald, Susan Li, Lawrence Colwell, John E. Fisher, Sharon Adamski, Alfred A. Reszka, Donald Kimmel & 5 others Frank Dininno, Susan P. Rohrer, Leonard P. Freedman, James M. Schaeffer, Milton L. Hammond

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The discovery, synthesis, and SAR of chromanes as ERα subtype selective ligands are described. X-ray studies revealed that the origin of the ERα-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).

Original languageEnglish
Pages (from-to)1675-1681
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume15
Issue number6
DOIs
Publication statusPublished - 15-03-2005
Externally publishedYes

Fingerprint

Scaffolds
Estrogen Receptors
Rats
Ligands
MCF-7 Cells
Cell growth
Ovariectomy
Bone Resorption
Estradiol
Assays
Bone
Substitution reactions
Cholesterol
X-Rays
Weights and Measures
X rays
Growth
Serum
diphenyl

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Tan, Q., Blizzard, T. A., Morgan, J. D., Birzin, E. T., Chan, W., Yang, Y. T., ... Hammond, M. L. (2005). Estrogen receptor ligands. Part 10: Chromanes: Old scaffolds for new SERAMs. Bioorganic and Medicinal Chemistry Letters, 15(6), 1675-1681. https://doi.org/10.1016/j.bmcl.2005.01.046
Tan, Qiang ; Blizzard, Timothy A. ; Morgan, Jerry D. ; Birzin, Elizabeth T. ; Chan, Wanda ; Yang, Yi Tien ; Pai, Lee Yuh ; Hayes, Edward C. ; Dasilva, Carolyn A. ; Warrier, Sudha ; Yudkovitz, Joel ; Wilkinson, Hilary A. ; Sharma, Nandini ; Fitzgerald, Paula M.D. ; Li, Susan ; Colwell, Lawrence ; Fisher, John E. ; Adamski, Sharon ; Reszka, Alfred A. ; Kimmel, Donald ; Dininno, Frank ; Rohrer, Susan P. ; Freedman, Leonard P. ; Schaeffer, James M. ; Hammond, Milton L. / Estrogen receptor ligands. Part 10 : Chromanes: Old scaffolds for new SERAMs. In: Bioorganic and Medicinal Chemistry Letters. 2005 ; Vol. 15, No. 6. pp. 1675-1681.
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abstract = "The discovery, synthesis, and SAR of chromanes as ERα subtype selective ligands are described. X-ray studies revealed that the origin of the ERα-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).",
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Tan, Q, Blizzard, TA, Morgan, JD, Birzin, ET, Chan, W, Yang, YT, Pai, LY, Hayes, EC, Dasilva, CA, Warrier, S, Yudkovitz, J, Wilkinson, HA, Sharma, N, Fitzgerald, PMD, Li, S, Colwell, L, Fisher, JE, Adamski, S, Reszka, AA, Kimmel, D, Dininno, F, Rohrer, SP, Freedman, LP, Schaeffer, JM & Hammond, ML 2005, 'Estrogen receptor ligands. Part 10: Chromanes: Old scaffolds for new SERAMs', Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 6, pp. 1675-1681. https://doi.org/10.1016/j.bmcl.2005.01.046

Estrogen receptor ligands. Part 10 : Chromanes: Old scaffolds for new SERAMs. / Tan, Qiang; Blizzard, Timothy A.; Morgan, Jerry D.; Birzin, Elizabeth T.; Chan, Wanda; Yang, Yi Tien; Pai, Lee Yuh; Hayes, Edward C.; Dasilva, Carolyn A.; Warrier, Sudha; Yudkovitz, Joel; Wilkinson, Hilary A.; Sharma, Nandini; Fitzgerald, Paula M.D.; Li, Susan; Colwell, Lawrence; Fisher, John E.; Adamski, Sharon; Reszka, Alfred A.; Kimmel, Donald; Dininno, Frank; Rohrer, Susan P.; Freedman, Leonard P.; Schaeffer, James M.; Hammond, Milton L.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 15, No. 6, 15.03.2005, p. 1675-1681.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Estrogen receptor ligands. Part 10

T2 - Chromanes: Old scaffolds for new SERAMs

AU - Tan, Qiang

AU - Blizzard, Timothy A.

AU - Morgan, Jerry D.

AU - Birzin, Elizabeth T.

AU - Chan, Wanda

AU - Yang, Yi Tien

AU - Pai, Lee Yuh

AU - Hayes, Edward C.

AU - Dasilva, Carolyn A.

AU - Warrier, Sudha

AU - Yudkovitz, Joel

AU - Wilkinson, Hilary A.

AU - Sharma, Nandini

AU - Fitzgerald, Paula M.D.

AU - Li, Susan

AU - Colwell, Lawrence

AU - Fisher, John E.

AU - Adamski, Sharon

AU - Reszka, Alfred A.

AU - Kimmel, Donald

AU - Dininno, Frank

AU - Rohrer, Susan P.

AU - Freedman, Leonard P.

AU - Schaeffer, James M.

AU - Hammond, Milton L.

PY - 2005/3/15

Y1 - 2005/3/15

N2 - The discovery, synthesis, and SAR of chromanes as ERα subtype selective ligands are described. X-ray studies revealed that the origin of the ERα-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).

AB - The discovery, synthesis, and SAR of chromanes as ERα subtype selective ligands are described. X-ray studies revealed that the origin of the ERα-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).

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DO - 10.1016/j.bmcl.2005.01.046

M3 - Article

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EP - 1681

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 6

ER -