The A-CD analogue of 16 beta,17 alpha-estriol is a potent and highly selective estrogen receptor beta agonist
Artikel i vetenskaplig tidskrift, 2013

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.

JOURNAL OF ORGANIC CHEMISTRY

SS DB

INSIGHTS

1983

ALPHA

KETONES

BINDING

V48

METABOLITES

P4155

LIGAND

Författare

Claire Sauvée

Göteborgs universitet

Anja Schäfer

Göteborgs universitet

Henrik Sundén

Göteborgs universitet

J. N. Ma

A. L. Gustavsson

E. S. Burstein

Roger Olsson

Göteborgs universitet

MedChemComm

2040-2503 (ISSN) 2040-2511 (eISSN)

Vol. 4 11 1439-1442

Ämneskategorier

Kemi

DOI

10.1039/c3md00194f