Lead Optimization of P5U and Urantide: Discovery of Novel Potent Ligands at the Urotensin-II Receptor

详细信息    查看全文

• 作者：Alfonso Carotenuto ; Luigia Auriemma ; Francesco Merlino ; Ali Munaim Yousif ; Daniela Marasco ; Antonio Limatola ; Pietro Campiglia ; Isabel Gomez-Monterrey ; Paolo Santicioli ; Stefania Meini ; Carlo A. Maggi ; Ettore Novellino ; Paolo Grieco
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：5965-5974
• 全文大小：372K
• ISSN：1520-4804

文摘

We have optimized 1 (P5U) and urantide, two important ligands at the h-UT receptor, designing several analogues by the exchange of the Tyr⁹ residue with different unnatural aromatic amino acids. This study allowed us to discover novel ligands with improved activity. In particular, the replacement of the Tyr⁹ residue by (pCN)Phe or (pNO₂)Phe within the urantide sequence led to compounds 13 (UPG-83) and 15 (UPG-95), respectively, which showed pure antagonist activity toward UT receptor in a rat aorta bioassay. More interestingly, the replacement of the Tyr⁹ in 1 sequence with the Btz or the (3,4-Cl)Phe residues led to superagonists 6 (UPG-100) and 10 (UPG-92) with pEC₅₀ values at least 1.4 log higher than that of 1, being the most potent UT agonists discovered to date. Compounds 10 and 13 showed also a good stability in a serum proteolytic assay. These ligands represent new useful tools to further characterize the urotensinergic system in human physiopathology.