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; Frank Dininno; Susan P. Rohrer; Leonard P. Freedman; James M. Schaeffer; Milton L. Hammond

doi:10.1016/j.bmcl.2005.01.046

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

Frank Dininno, Susan P. Rohrer, Leonard P. Freedman, James M. Schaeffer, Milton L. Hammond

^*Corresponding author for this work

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

52 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 language	English
Pages (from-to)	1675-1681
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	15
Issue number	6
DOIs	https://doi.org/10.1016/j.bmcl.2005.01.046
Publication status	Published - 15-03-2005
Externally published	Yes

All Science Journal Classification (ASJC) codes

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

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10.1016/j.bmcl.2005.01.046

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Tan, Q., Blizzard, T. A., Morgan, J. D., Birzin, E. T., Chan, W., Yang, Y. T., Pai, L. Y., Hayes, E. C., Dasilva, C. A., Warrier, S., Yudkovitz, J., Wilkinson, H. A., Sharma, N., Fitzgerald, P. M. D., Li, S., Colwell, L., Fisher, J. E., Adamski, S., Reszka, A. A., ... 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

@article{692674d9db034a1da759da37db8b7105,

title = "Estrogen receptor ligands. Part 10: Chromanes: Old scaffolds for new SERAMs",

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).",

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

year = "2005",

month = mar,

day = "15",

doi = "10.1016/j.bmcl.2005.01.046",

language = "English",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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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

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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

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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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JF - Bioorganic and Medicinal Chemistry Letters

IS - 6

ER -

Estrogen receptor ligands. Part 10: Chromanes: Old scaffolds for new SERAMs

Abstract

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