Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 103, Issue -, Pages 312-324Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.08.048
Keywords
Protein-protein interaction inhibitors; Eph-ephrin antagonists; EphA2; Anti-angiogenic agents; Oral bioavailability; Bile acids
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Funding
- Ministero dell'Universita e della Ricerca, Futuro in Ricerca program [RBFR1OFXCP]
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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 Delta(5)-cholenoyl-amino acid conjugates as Eph-ephrin antagonists. As a major achievement of our exploration, we identified N-(3 beta-hydroxy-Delta(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. (C) 2015 Elsevier Masson SAS. All rights reserved.
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