Synthesis and receptor binding in trans-CD ring-fused A-CD estrogens: Comparison with the cis-fused isomers

Abstract

Ligands which selectively activate only one of the estrogen receptors, ERα or ERβ, are current pharmaceutical targets. Previously, we have reported on substituted cis A-CD ligands in which the B-ring of the steroidal structure has been removed and cis refers the stereochemistry of the CD ring junction as compared to trans in estradiol. These compounds often showed good potency and selectivity for ERβ. Here we report the synthesis and binding affinities for a similar series of trans A-CD ligands, and compare them to the cis-series. Counterintuitively, trans A-CD ligands, which are structurally more closely related to the natural ligand estradiol, show weaker binding and less β-selectivity than their cis-counterparts.

A–C Estrogens as Potent and Selective Estrogen Receptor-Beta Agonists (SERBAs) to Enhance Memory Consolidation under Low-Estrogen Conditions

“…Herein is reported the optimization and characterization of a related class of molecules, comprised of a 4-hydroxymethyl-cyclohexane ring tethered to a phenol ring, making it an A–C estrogen that closely resembles the naturally occurring estrogen molecule but lacks the B and D rings (Figure b–d). Whereas A–CD estrogens have been widely studied and reported to have up to 15-fold selectivity for ERβ, − the simpler A–C estrogens reported herein show even higher selectivity for ERβ over ERα. These A–C estrogens represent a surprisingly simple yet novel class of isoform selective ERβ agonists, with potential for treating age-related memory decline in postmenopausal women.…”