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Prodrug Design For The Potent Cardiovascular Agent Nω-hydroxy-L-arginine (NOHA): Synthetic Approaches And Physicochemical Characterization.
D. Schade, J. Kotthaus, N. Klein, Joscha Kotthaus, B. Clement
Published 2011 · Chemistry, Medicine
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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.
This paper references
N(G)-aminoguanidines from primary amines and the preparation of nitric oxide synthase inhibitors.
N. Martin (2008)
Structure-activity relationship of novel and known inhibitors of human dimethylarginine dimethylaminohydrolase-1: alkenyl-amidines as new leads.
J. Kotthaus (2008)
The enzymatic reduction of hydroxyguanidine.
J. Walker (1959)
Hydrolysis in drug and prodrug metabolism : chemistry, biochemistry, and enzymology
B. Testa (2003)
Galactosyl derivatives of L-arginine and D-arginine: synthesis, stability, cell permeation, and nitric oxide production in pituitary GH3 cells.
D. Melisi (2006)
Expedient synthesis of aminooxylated-carbohydrates for chemoselective access of glycoconjugates
O. Renaudet (2001)
Nδ-Methylated l-arginine derivatives and their effects on the nitric oxide generating system
J. Kotthaus (2008)
ARGINASE: A CRITICAL REGULATOR OF NITRIC OXIDE SYNTHESIS AND VASCULAR FUNCTION
W. Durante (2007)
Synthesis of 15Nω‐Hydroxy‐L‐arginine and ESR and 15N‐NMR Studies for the Elucidation of the Molecular Mechanism of Enzymic Nitric Oxide Formation from L‐Arginine
B. Clement (1994)
On the mechanism of the nitric oxide synthase-catalyzed conversion of N omega-hydroxyl-L-arginine to citrulline and nitric oxide.
H. Korth (1994)
New Treatment Option for Second-Stage African Sleeping Sickness: In Vitro and In Vivo Efficacy of Aza Analogs of DB289
T. Wenzler (2009)
Reduction of Nω-hydroxy-l-arginine to l-arginine by pig liver microsomes, mitochondria, and human liver microsomes
B. Clement (2006)
Peracid oxidation of an N-hydroxyguanidine compound: a chemical model for the oxidation of N omega-hydroxyl-L-arginine by nitric oxide synthase.
J. Fukuto (1993)
Microwave-assisted preparations of amidrazones and amidoximes.
A. Katritzky (2006)
Reduction of N(ω)-hydroxy-L-arginine by the mitochondrial amidoxime reducing component (mARC).
J. Kotthaus (2011)
Cytochrome P450 dependent N-hydroxylation of a guanidine (debrisoquine), microsomal catalysed reduction and further oxidation of the N-hydroxy-guanidine metabolite to the urea derivative. Similarity with the oxidation of arginine to citrulline and nitric oxide.
B. Clement (1993)
Human Enteric Microsomal CYP4F Enzymes O-Demethylate the Antiparasitic Prodrug Pafuramidine
M. Wang (2007)
Methodology for the preparation of N-guanidino-modified arginines and related derivatives
F. Wagenaar (1993)
Oxidation of N-hydroxyguanidines by copper(II): model systems for elucidating the physiological chemistry of the nitric oxide biosynthetic intermediate N-hydroxyl-L-arginine.
J. Cho (2003)
Hydroxyguanidines inhibit peroxynitrite-induced oxidation.
G. Southan (1998)
Modulating the NO generating system from a medicinal chemistry perspective: current trends and therapeutic options in cardiovascular disease.
D. Schade (2010)
NG-hydroxyguanidines from primary amines.
N. Martin (2006)
Über O‐acylierte Hydroximsäure‐ester und ihre Spaltung zu unsubstituierten O‐Acylhydroxylaminen . X. Mitteilung über Hydroxylamin‐Derivate
G. Zinner (1960)
Chemical oxidation of N-hydroxyguanidine compounds. Release of nitric oxide, nitroxyl and possible relationship to the mechanism of biological nitric oxide generation.
J. Fukuto (1992)
New NO‐Donors with Antithrombotic and Vasodilating Activities, Part 16 3‐Amino‐1,2,4‐oxadiazol‐5‐ones as Prodrugs for Hydroxyguanidines
K. Rehse (1996)
Nitric oxide donors: chemical activities and biological applications.
P. Wang (2002)
Peroxynitrite: biochemistry, pathophysiology and development of therapeutics
C. Szabo (2007)
Endothelial function and oxidative stress in cardiovascular diseases.
Y. Higashi (2009)
Novel substrates and inhibitors of peptidylglycine alpha-amidating monooxygenase.
A. Katopodis (1990)
Nitric oxide and atherosclerosis: an update.
C. Napoli (2006)
Glycosylated diazeniumdiolates: a novel class of enzyme-activated nitric oxide donors
Xuejun Wu (2001)
Microsomal catalyzed N-hydroxylation of guanabenz and reduction of the N-hydroxylated metabolite: characterization of the two reactions and genotoxic potential of guanoxabenz.
B. Clement (1996)
N omega-hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine.
D. Stuehr (1991)
Vascular System: Role of Nitric Oxide in Cardiovascular Diseases
K. Bian (2008)
A versatile one-Pot synthesis of 1,3-substituted guanidines from carbamoyl isothiocyanates
Synthesis of mono- and symmetrical di-N-hydroxy- and N-aminoguanidines.
A. Katritzky (2006)
Chemistry of N-hydroxy-L-arginine.
J. Fukuto (1996)
Arginine: beyond protein.
S. M. Morris (2006)
Electrochemical and peroxidase oxidation study of N'-hydroxyguanidine derivatives as NO donors.
T. Cai (2002)
Microsomal cytochrome P450 dependent oxidation of N-hydroxyguanidines, amidoximes, and ketoximes: mechanism of the oxidative cleavage of their C=N(OH) bond with formation of nitrogen oxides.
A. Jousserandot (1998)
METABOLISM OF N-HYDROXYGUANIDINES (N-HYDROXYDEBRISOQUINE) IN HUMAN AND PORCINE HEPATOCYTES: REDUCTION AND FORMATION OF GLUCURONIDES
A. K. Froehlich (2005)
The Peptidylglycine α‐Amidating Monooxygenase (PAM): A Novel Prodrug Strategy for Amidoximes and N‐Hydroxyguanidines?
D. Schade (2009)
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Jing Xiang (2016)
Design, Synthesis, and Bioactivation of O-Glycosylated Prodrugs of the Natural Nitric Oxide Precursor N(ω)-Hydroxy-l-arginine.
Felix-A Litty (2016)
Synthesis of phidianidines A and B.
H. Lin (2012)
1-(2-Mercaptobenzenesulfonyl)-3-hydroxyguanidines--novel potent antiproliferatives, synthesis and in vitro biological activity.
Kamil Brożewicz (2012)
Pharmacokinetics and Pharmacodynamics of Promising Arginase Inhibitors
K. Abdelkawy (2016)
Computational analysis of nitric oxide biotransport to red blood cell in the presence of free hemoglobin and NO donor.
Prabhakar Deonikar (2014)
Methylated N(ω)-hydroxy-L-arginine analogues as mechanistic probes for the second step of the nitric oxide synthase-catalyzed reaction.
Kristin Jansen Labby (2013)
Preparation, Reactivity, and Synthetic Utility of Simple Benzotriazole Derivatives
Romaric Gérardy (2015)
Zanamivir Amidoxime- and N-Hydroxyguanidine-Based Prodrug Approaches to Tackle Poor Oral Bioavailability.
D. Schade (2015)
Development of novel potent orally bioavailable oseltamivir derivatives active against resistant influenza A.
D. Schade (2014)
A new class of NO-donor pro-drugs triggered by γ-glutamyl transpeptidase with potential for reno-selective vasodilatation.
Q. Zhang (2013)
Aromatic bis-N-hydroxyguanidinium derivatives: synthesis, biophysical, and biochemical evaluations.
Amila Kahvedžić (2013)