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The A-CD analogue of 16 beta,17 alpha-estriol is a potent and highly selective estrogen receptor beta agonist

Sauvee, Claire ; Schafer, Anja ; Sunden, Henrik ; Ma, Jian-Nong ; Gustavsson, Anna-Lena ; Burstein, Ethan S. and Olsson, Roger LU (2013) In MedChemComm 4(11). p.1439-1442
Abstract
Selective estrogen receptor beta (ER beta) agonists display neuroprotective properties in animal models and hold promise in the treatment of neurodegenerative diseases. In our quest to design, synthesize and evaluate potent and safe ER beta agonists, we focused on making an analogue of 16 beta,17 alpha-estriol (16,17-epiestriol), a potent and one of the most ER beta selective endogenous estrogens reported. Herein we disclose the synthesis and in vitro evaluation of an analogue based on the recently introduced A-CD scaffold. A 14-step synthesis based on the Hajos-Parrish ketone resulted in the discovery of (1S,2S,3aS,5S,7aS)-5-(4-hydroxyphenyl)-7a-methyloctahydro-1H-indene-1,2-diol (15). This A-CD analogue of 16 beta, 17 alpha-estriol is a... (More)
Selective estrogen receptor beta (ER beta) agonists display neuroprotective properties in animal models and hold promise in the treatment of neurodegenerative diseases. In our quest to design, synthesize and evaluate potent and safe ER beta agonists, we focused on making an analogue of 16 beta,17 alpha-estriol (16,17-epiestriol), a potent and one of the most ER beta selective endogenous estrogens reported. Herein we disclose the synthesis and in vitro evaluation of an analogue based on the recently introduced A-CD scaffold. A 14-step synthesis based on the Hajos-Parrish ketone resulted in the discovery of (1S,2S,3aS,5S,7aS)-5-(4-hydroxyphenyl)-7a-methyloctahydro-1H-indene-1,2-diol (15). This A-CD analogue of 16 beta, 17 alpha-estriol is a highly selective (500-fold) ER beta full agonist over ER alpha with a pEC(50) of 7.7 at ER beta. Molecular modelling suggests that 15 turns around in the ligand-binding domain compared to estriol, thus the 7a-methyl occupies the alpha-face, which might explain the high selectivity. (Less)
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organization
publishing date
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Contribution to journal
publication status
published
subject
in
MedChemComm
volume
4
issue
11
pages
1439 - 1442
publisher
Royal Society of Chemistry
external identifiers
  • wos:000326244600003
  • scopus:84886787950
ISSN
2040-2511
DOI
10.1039/c3md00194f
language
English
LU publication?
yes
id
d5da0cc6-f787-4e70-b547-0123cbf8ee24 (old id 4204574)
date added to LUP
2016-04-01 10:01:58
date last changed
2020-01-05 04:14:40
@article{d5da0cc6-f787-4e70-b547-0123cbf8ee24,
  abstract     = {Selective estrogen receptor beta (ER beta) agonists display neuroprotective properties in animal models and hold promise in the treatment of neurodegenerative diseases. In our quest to design, synthesize and evaluate potent and safe ER beta agonists, we focused on making an analogue of 16 beta,17 alpha-estriol (16,17-epiestriol), a potent and one of the most ER beta selective endogenous estrogens reported. Herein we disclose the synthesis and in vitro evaluation of an analogue based on the recently introduced A-CD scaffold. A 14-step synthesis based on the Hajos-Parrish ketone resulted in the discovery of (1S,2S,3aS,5S,7aS)-5-(4-hydroxyphenyl)-7a-methyloctahydro-1H-indene-1,2-diol (15). This A-CD analogue of 16 beta, 17 alpha-estriol is a highly selective (500-fold) ER beta full agonist over ER alpha with a pEC(50) of 7.7 at ER beta. Molecular modelling suggests that 15 turns around in the ligand-binding domain compared to estriol, thus the 7a-methyl occupies the alpha-face, which might explain the high selectivity.},
  author       = {Sauvee, Claire and Schafer, Anja and Sunden, Henrik and Ma, Jian-Nong and Gustavsson, Anna-Lena and Burstein, Ethan S. and Olsson, Roger},
  issn         = {2040-2511},
  language     = {eng},
  number       = {11},
  pages        = {1439--1442},
  publisher    = {Royal Society of Chemistry},
  series       = {MedChemComm},
  title        = {The A-CD analogue of 16 beta,17 alpha-estriol is a potent and highly selective estrogen receptor beta agonist},
  url          = {http://dx.doi.org/10.1039/c3md00194f},
  doi          = {10.1039/c3md00194f},
  volume       = {4},
  year         = {2013},
}