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Zanamivir Amidoxime- And N-Hydroxyguanidine-Based Prodrug Approaches To Tackle Poor Oral Bioavailability.
D. Schade, J. Kotthaus, Lukas Riebling, Joscha Kotthaus, H. Müller-Fielitz, W. Raasch, A. Hoffmann, M. Schmidtke, B. Clement
Published 2015 · Chemistry, Medicine
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The neuraminidase (NA) inhibitor zanamivir (1) is potently active against a broad panel of influenza A and B strains, including mutant viruses, but suffers from pharmacokinetic (PK) shortcomings. Here, distinct prodrug approaches are described that aimed at overcoming zanamivir's lack of oral bioavailability. Lowering the high basicity of the 4-guanidino group in zanamivir and of a bioisosteric 4-acetamidine analog (5) by N-hydroxylation was deemed to be a plausible tactic. The carboxylic acid and glycerol side chain were also masked with different ester groups. The bioisosteric amidine 5 turned out to be potently active against a panel of H1N1 (IC50 = 2-10 nM) and H3N2 (IC50 = 5-10 nM) influenza A viruses (NA inhibition assay). In vitro PK studies showed that all prodrugs were highly soluble, exhibited low protein binding, and were bioactivated by N-reduction to the respective guanidines and amidines. The most promising prodrug candidates, amidoxime ester 7 and N-hydroxyguanidine ester 8, were subjected to in vivo bioavailability studies. Unfortunately, both prodrugs were not orally bioavailable to a convincing degree (F ≤ 3.7%, rats). This finding questions the general feasibility of improving the oral bioavailability of 1 by lipophilicity-increasing prodrug strategies, and suggests that intrinsic structural features represent key hurdles.
This paper references
The Role of Clinical Pharmacology in Supporting the Emergency Use Authorization of an Unapproved Anti‐Influenza Drug, Peramivir
V. Arya (2010)
Prodrug design for the potent cardiovascular agent Nω-hydroxy-L-arginine (NOHA): synthetic approaches and physicochemical characterization.
D. Schade (2011)
Supply of Neuraminidase Inhibitors Related to Reduced Influenza A (H1N1) Mortality during the 2009–2010 H1N1 Pandemic: An Ecological Study
Paula E. Miller (2012)
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)
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)
Novel neuraminidase inhibitors: identification, biological evaluation and investigations of the binding mode.
J. Kirchmair (2011)
Human infection with a novel avian-origin influenza A (H7N9) virus.
Rongbao Gao (2013)
Complementary assays helping to overcome challenges for identifying neuraminidase inhibitors
Martina Richter (2015)
A rapid assay for evaluation of antiviral activity against coxsackie virus B3, influenza virus A, and herpes simplex virus type 1.
M. Schmidtke (2001)
Surveillance for Neuraminidase Inhibitor Resistance among Human Influenza A and B Viruses Circulating Worldwide from 2004 to 2008
Tiffany G. Sheu (2008)
Antiviral agents active against influenza A viruses
E. Clercq (2006)
Neuraminidase inhibitor resistance in influenza viruses and laboratory testing methods.
H. Nguyen (2012)
Laninamivir Prodrug CS-8958, a Long-Acting Neuraminidase Inhibitor, Shows Superior Anti-Influenza Virus Activity after a Single Administration
Shuku Kubo (2010)
A DNA transfection system for generation of influenza A virus from eight plasmids.
E. Hoffmann (2000)
4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuraminidase) and of growth of a wide range of influenza A and B viruses in vitro.
J. M. Woods (1993)
Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic
G. Smith (2009)
Pharmacokinetics of Zanamivir After Intravenous, Oral, Inhaled or Intranasal Administration to Healthy Volunteers
L. Cass (1999)
METABOLISM OF N-HYDROXYGUANIDINES (N-HYDROXYDEBRISOQUINE) IN HUMAN AND PORCINE HEPATOCYTES: REDUCTION AND FORMATION OF GLUCURONIDES
A. K. Froehlich (2005)
Neuraminidase Inhibitors: Zanamivir and Oseltamivir
I. McNicholl (2001)
Increasing oral absorption of polar neuraminidase inhibitors: a prodrug transporter approach applied to oseltamivir analogue.
D. Gupta (2013)
Antivirals targeting influenza A virus.
K. Das (2012)
The Emergency Use Authorization of peramivir for treatment of 2009 H1N1 influenza.
D. Birnkrant (2009)
Development of novel potent orally bioavailable oseltamivir derivatives active against resistant influenza A.
D. Schade (2014)
Zanamivir: from drug design to the clinic.
M. Elliott (2001)
Are We Ready for Pandemic Influenza?
R. Webby (2003)
BCX-1812 (RWJ-270201): discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design.
Y. Babu (2000)
Emergence of a novel swine-origin influenza A (H1N1) virus in humans.
Fatimah S. Dawood (2009)
A versatile one-Pot synthesis of 1,3-substituted guanidines from carbamoyl isothiocyanates
S-2-Naphthylmethyl thioacetimidate hydrobromide: A new odorless reagent for the mild synthesis of substituted acetamidines
B. G. Shearer (1997)
NG-hydroxyguanidines from primary amines.
N. Martin (2006)
Antiviral potential and molecular insight into neuraminidase inhibiting diarylheptanoids from Alpinia katsumadai.
U. Grienke (2010)
Different neuraminidase inhibitor susceptibilities of human H1N1, H1N2, and H3N2 influenza A viruses isolated in Germany from 2001 to 2005/2006.
Katja Bauer (2009)
Stereoselective synthesis of 1,2-diols by the cycloadditive strategy: total synthesis of (±)-exo-brevicomin and (±)-and (–)-pestalotin
J. Zhang (1991)
Enabling the intestinal absorption of highly polar antiviral agents: ion-pair facilitated membrane permeation of zanamivir heptyl ester and guanidino oseltamivir.
J. Miller (2010)
Enhancing the intestinal membrane permeability of zanamivir: a carrier mediated prodrug approach.
S. V. Gupta (2011)
Laninamivir and its Prodrug, CS-8958: Long-Acting Neuraminidase Inhibitors for the Treatment of Influenza
M. Yamashita (2010)
Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations
B. Davies (2010)
Intramolecular ion-pair prodrugs of zanamivir and guanidino-oseltamivir.
K. Liu (2011)
Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors.
C. U. Kim (1998)
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The design, synthesis and biological evaluation of carbohydrate-based probes of proteins
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Advanced Prodrug Strategies in Nucleoside and Non-Nucleoside Antiviral Agents: A Review of the Recent Five Years
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Evaluation of amidoxime derivatives as prodrug candidates of potent bis-cationic antimalarials.
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Discovery and Characterization of Diazenylaryl Sulfonic Acids as Inhibitors of Viral and Bacterial Neuraminidases
A. Hoffmann (2017)
Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue.
T. Incecayir (2016)
High-performance Countercurrent Chromatography to Access Rhodiola rosea Influenza Virus Inhibiting Constituents.
J. Langeder (2020)
Binding and Proton Blockage by Amantadine Variants of the Influenza M2WT and M2S31N Explained.
Christina Tzitzoglaki (2017)
Platform for determining the inhibition profile of neuraminidase inhibitors in an influenza virus N1 background.
A. Hoffmann (2016)
Discovery of prenylated flavonoids with dual activity against influenza virus and Streptococcus pneumoniae
U. Grienke (2016)
Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited.
Antonios Drakopoulos (2017)
Amantadine copper(II) chloride conjugate with possible implementation in influenza virus inhibition
C. N. Banti (2020)
A Novel Prodrug of a nNOS Inhibitor with Improved Pharmacokinetic Potential
C. Maccallini (2020)