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 t...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2015-10, Vol.103, p.312-324
Main Authors: Castelli, Riccardo, Tognolini, Massimiliano, Vacondio, Federica, Incerti, Matteo, Pala, Daniele, Callegari, Donatella, Bertoni, Simona, Giorgio, Carmine, Hassan-Mohamed, Iftiin, Zanotti, Ilaria, Bugatti, Antonella, Rusnati, Marco, Festuccia, Claudio, Rivara, Silvia, Barocelli, Elisabetta, Mor, Marco, Lodola, Alessio
Format: Article
Language:English
Subjects:
Anti-angiogenic agents
Bile acids
EphA2
Eph–ephrin antagonists
Oral bioavailability
Protein–protein interaction inhibitors
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Summary: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 Δ5-cholenoyl-amino acid conjugates as Eph–ephrin antagonists. As a major achievement of our exploration, we identified N-(3β-hydroxy-Δ5-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. [Display omitted] •A series of Δ5-cholenoyl-amino acid conjugates was designed and synthesized.•Most of the compounds resulted able to displace ephrin-A1 from the EphA2 receptor.•The l-tryptophan derivative UniPR1331 displayed anti-angiogenic properties in vitro.•UniPR1331 resulted bioavailable in mice by the oral route.•UniPR1331 resulted inactive on GPCR and nuclear receptors targeted by bile acids.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2015.08.048