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

På svenska

Author

  • Claire Sauvee
  • Anja Schafer
  • Henrik Sunden
  • Jian-Nong Ma
  • Anna-Lena Gustavsson
  • Ethan S. Burstein
  • Roger Olsson

Summary, in English

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.

Publishing year

2013

Language

English

Pages

1439-1442

Publication/Series

MedChemComm

Volume

4

Issue

11

Document type

Journal article

Publisher

Royal Society of Chemistry

Topic

  • Medicinal Chemistry

Status

Published

Research group

  • Chemical Biology and Therapeutics

ISBN/ISSN/Other

  • ISSN: 2040-2511