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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

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

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Läkemedelskemi
Originalspråkengelska
Sidor (från-till)1439-1442
TidskriftMedChemComm
Volym4
Utgivningsnummer11
StatusPublished - 2013
PublikationskategoriForskning
Peer review utfördJa