Δ5-Cholenoyl-amino acids as selective and orally available antagonists of the Eph–ephrin system.

The Eph receptor–ephrin 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 structure–activity relationships of a class of Δ 5 -cholenoyl-amino acid conjugates as Eph–ephrin antagonists. As a major achievement of our exploration, we identified N -(3β-hydroxy-Δ 5 -cholen-24-oyl)- l -tryptophan (UniPR1331) as the first small molecule antagonist of the Eph–ephrin 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. [ABSTRACT FROM AUTHOR]