Δ5-Cholenoyl-amino acids as selective and orally available antagonists of the Epheephrin system

The Eph receptoreephrin system is an emerging target for the development of novel anti-angiogenic therapies. Research programs aimed at developing small-molecule antagonists of the Eph receptors are still in their initial stage as available compounds suffer from pharmacological drawbacks, limiting their application in vitro and in vivo. In the present work, we report the design, synthesis and evaluation of structureeactivity relationships of a class of D5-cholenoyl-amino acid conjugates as Epheephrin antagonists. As a major achievement of our exploration, we identified N-(3b-hydroxy-D5-cholen-24-oyl)-Ltryptophan (UniPR1331) as the first small molecule antagonist of the Epheephrin system effective as an anti-angiogenic agent in endothelial cells, bioavailable in mice by the oral route and devoid of biological activity on G protein-coupled and nuclear receptors targeted by bile acid derivatives.