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Issue 14, 2011
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Prodrug design for the potent cardiovascular agent Nω-hydroxy-l-arginine (NOHA): Synthetic approaches and physicochemical characterization

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Abstract

N ω-Hydroxy-L-arginine (NOHA)—the physiological nitric oxide precursor—is the intermediate of NO synthase (NOS) catalysis. Besides the important fact of releasing NO mainly at the NOS-side of action, NOHA also represents a potent inhibitor of arginases, making it an ideal therapeutic tool to treat cardiovascular diseases that are associated with endothelial dysfunction. Here, we describe an approach to impart NOHA drug-like properties, particularly by wrapping up the chemically and metabolically instable N-hydroxyguanidine moiety with different prodrug groups. We present synthetic routes that deliver several more or less highly substituted NOHA derivatives in excellent yields. Versatile prodrug strategies were realized, including novel concepts of bioactivation. Prodrug candidates were primarily investigated regarding their hydrolytic and oxidative stabilities. Within the scope of this work, we essentially present the first prodrug approaches for an interesting pharmacophoric moiety, i.e., N-hydroxyguanidine.

Graphical abstract: Prodrug design for the potent cardiovascular agent Nω-hydroxy-l-arginine (NOHA): Synthetic approaches and physicochemical characterization

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Supplementary files

Article information


Submitted
06 Dec 2010
Accepted
20 Apr 2011
First published
21 Apr 2011

Org. Biomol. Chem., 2011,9, 5249-5259
Article type
Paper

Prodrug design for the potent cardiovascular agent Nω-hydroxy-L-arginine (NOHA): Synthetic approaches and physicochemical characterization

D. Schade, J. Kotthaus, N. Klein, J. Kotthaus and B. Clement, Org. Biomol. Chem., 2011, 9, 5249
DOI: 10.1039/C0OB01117G

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