title: Prodrug design for the potent cardiovascular agent Nω-hydroxy-L-arginine (NOHA): synthetic approaches and physicochemical characterization.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel, Gutenbergstraße 76-78, D-24118 Kiel, Germany. dschade@sanfordburnham.org
authors.forename: Dennis
authors.initials: D
authors.lastname: Schade
authors.forename: Jürke
authors.initials: J
authors.lastname: Kotthaus
authors.forename: Nikola
authors.initials: N
authors.lastname: Klein
authors.forename: Joscha
authors.initials: J
authors.lastname: Kotthaus
authors.forename: Bernd
authors.initials: B
authors.lastname: Clement
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D002317:Cardiovascular Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002627:Chemistry, Physical; D015195:Drug Design; D006863:Hydrogen-Ion Concentration; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D002317:Cardiovascular Agents; C404735:N(omega)-hydroxynorarginine; D011355:Prodrugs; D001120:Arginine