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Design of a Highly Selective and Potent Class of Non-planar Estrogen Receptor Agonists

Sunden, Henrik ; Ma, Jian-Nong ; Hansen, Lars K. ; Gustavsson, Anna-Lena ; Burstein, Ethan S. and Olsson, Roger LU (2013) In ChemMedChem 8(8). p.1283-1294
Abstract
Selective activation of the estrogen receptor (ER) could be a safe approach to hormone replacement therapy for both women and men, in contrast to the estrogens currently used for women which activate both ER and ER, occasionally causing severe side effects. cis-10-SR, was shown to have an EC50 value of <1nM, potency 100-fold higher than that of AC-131. Even more interestingly, compound trans-10-SS exhibited 1000-fold ER/ER selectivity while still maintaining good potency (approximate to 10nM). In addition, trans-10-SS showed only partial agonist activity (30-60% Eff.) toward ER at 10M. trans-10-SS appears to be the first molecule to take advantage of both conservative amino acid differences found in the - and -faces of the binding... (More)
Selective activation of the estrogen receptor (ER) could be a safe approach to hormone replacement therapy for both women and men, in contrast to the estrogens currently used for women which activate both ER and ER, occasionally causing severe side effects. cis-10-SR, was shown to have an EC50 value of <1nM, potency 100-fold higher than that of AC-131. Even more interestingly, compound trans-10-SS exhibited 1000-fold ER/ER selectivity while still maintaining good potency (approximate to 10nM). In addition, trans-10-SS showed only partial agonist activity (30-60% Eff.) toward ER at 10M. trans-10-SS appears to be the first molecule to take advantage of both conservative amino acid differences found in the - and -faces of the binding cavities of ER and ER beta. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
asymmetric synthesis, neurological agents, estrogen receptors, modulators, Parkinson's disease
in
ChemMedChem
volume
8
issue
8
pages
1283 - 1294
publisher
Wiley-Blackwell
external identifiers
  • wos:000322339400011
  • scopus:84881026267
  • pmid:23784708
ISSN
1860-7187
DOI
10.1002/cmdc.201300175
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Neuronal Survival (013212041)
id
88469b75-9479-416c-98dd-a6720110aefb (old id 4042734)
date added to LUP
2016-04-01 10:52:09
date last changed
2020-01-12 06:00:24
@article{88469b75-9479-416c-98dd-a6720110aefb,
  abstract     = {Selective activation of the estrogen receptor (ER) could be a safe approach to hormone replacement therapy for both women and men, in contrast to the estrogens currently used for women which activate both ER and ER, occasionally causing severe side effects. cis-10-SR, was shown to have an EC50 value of &lt;1nM, potency 100-fold higher than that of AC-131. Even more interestingly, compound trans-10-SS exhibited 1000-fold ER/ER selectivity while still maintaining good potency (approximate to 10nM). In addition, trans-10-SS showed only partial agonist activity (30-60% Eff.) toward ER at 10M. trans-10-SS appears to be the first molecule to take advantage of both conservative amino acid differences found in the - and -faces of the binding cavities of ER and ER beta.},
  author       = {Sunden, Henrik and Ma, Jian-Nong and Hansen, Lars K. and Gustavsson, Anna-Lena and Burstein, Ethan S. and Olsson, Roger},
  issn         = {1860-7187},
  language     = {eng},
  number       = {8},
  pages        = {1283--1294},
  publisher    = {Wiley-Blackwell},
  series       = {ChemMedChem},
  title        = {Design of a Highly Selective and Potent Class of Non-planar Estrogen Receptor Agonists},
  url          = {http://dx.doi.org/10.1002/cmdc.201300175},
  doi          = {10.1002/cmdc.201300175},
  volume       = {8},
  year         = {2013},
}