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Development Of Novel Potent Orally Bioavailable Oseltamivir Derivatives Active Against Resistant Influenza A.

D. Schade, Joscha Kotthaus, Lukas Riebling, J. Kotthaus, H. Müller-Fielitz, W. Raasch, O. Koch, Nora Seidel, M. Schmidtke, B. Clement
Published 2014 · Chemistry, Medicine

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With the emergence of oseltamivir-resistant influenza viruses and in view of a highly pathogenic flu pandemic, it is important to develop new anti-influenza agents. Here, the development of neuraminidase (NA) inhibitors that were designed to overcome resistance mechanisms along with unfavorable pharmacokinetic (PK) properties is described. Several 5-guanidino- and 5-amidino-based oseltamivir derivatives were synthesized and profiled for their anti-influenza activity and in vitro and in vivo PK properties. Amidine 6 and guanidine 7 were comparably effective against a panel of different A/H1N1 and A/H3N2 strains and also inhibited mutant A/H1N1 neuraminidase. Among different prodrug strategies pursued, a simple amidoxime ethyl ester (9) exhibited a superior PK profile with an oral bioavailability of 31% (rats), which is comparable to oseltamivir (36%). Thus, bioisosteric replacement of the 5-guanidine with an acetamidine-in the form of its N-hydroxy prodrug-successfully tackled the two key limitations of currently used NA inhibitors, as exemplified with oseltamivir.
This paper references
10.1016/0006-2952(93)90616-5
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)
10.1016/j.antiviral.2009.01.006
Different neuraminidase inhibitor susceptibilities of human H1N1, H1N2, and H3N2 influenza A viruses isolated in Germany from 2001 to 2005/2006.
Katja Bauer (2009)
World Health Organization Influenza Fact Sheet 211; World Health Organization: Geneva
(2009)
10.1124/dmd.105.004572
METABOLISM OF N-HYDROXYGUANIDINES (N-HYDROXYDEBRISOQUINE) IN HUMAN AND PORCINE HEPATOCYTES: REDUCTION AND FORMATION OF GLUCURONIDES
A. K. Froehlich (2005)
10.1039/P19910002627
Stereoselective synthesis of 1,2-diols by the cycloadditive strategy: total synthesis of (±)-exo-brevicomin and (±)-and (–)-pestalotin
J. Zhang (1991)
CS-8958: longacting neuraminidase inhibitors for the treatment of influenza
M Yamashita (2010)
10.1016/S0040-4039(96)02268-X
S-2-Naphthylmethyl thioacetimidate hydrobromide: A new odorless reagent for the mild synthesis of substituted acetamidines
B. G. Shearer (1997)
10.1021/jm901440f
Antiviral potential and molecular insight into neuraminidase inhibiting diarylheptanoids from Alpinia katsumadai.
U. Grienke (2010)
10.1128/AAC.42.3.647
Identification of GS 4104 as an Orally Bioavailable Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071
W. Li (1998)
10.2165/00003088-199936001-00001
Pharmacokinetics of Zanamivir After Intravenous, Oral, Inhaled or Intranasal Administration to Healthy Volunteers
L. Cass (1999)
10.1038/clpt.2010.187
The Role of Clinical Pharmacology in Supporting the Emergency Use Authorization of an Unapproved Anti‐Influenza Drug, Peramivir
V. Arya (2010)
10.3851/IMP2067
Neuraminidase inhibitor resistance in influenza viruses and laboratory testing methods.
H. Nguyen (2012)
10.1021/JA073992I
Synthesis of tamiflu and its phosphonate congeners possessing potent anti-influenza activity.
J. Shie (2007)
10.1124/DMD.31.5.645
Characterization of in vitro biotransformation of new, orally active, direct thrombin inhibitor ximelagatran, an amidoxime and ester prodrug.
B. Clement (2003)
10.1021/JM0002679
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)
10.1093/OXFORDJOURNALS.AJE.A118408
A SIMPLE METHOD OF ESTIMATING FIFTY PER CENT ENDPOINTS
L. Reed (1938)
10.1021/jm300455c
Antivirals targeting influenza A virus.
K. Das (2012)
10.1021/jm3008486
Development of oseltamivir phosphonate congeners as anti-influenza agents.
T. Cheng (2012)
10.1128/AAC.41.9.1949
Penetration of GS4071, a novel influenza neuraminidase inhibitor, into rat bronchoalveolar lining fluid following oral administration of the prodrug GS4104.
E. Eisenberg (1997)
10.1016/j.bmc.2011.01.066
Synthesis and biological evaluation of L-valine-amidoximeesters as double prodrugs of amidines.
Joscha Kotthaus (2011)
10.1128/AAC.37.7.1473
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)
10.1371/journal.pone.0043491
Supply of Neuraminidase Inhibitors Related to Reduced Influenza A (H1N1) Mortality during the 2009–2010 H1N1 Pandemic: An Ecological Study
Paula E. Miller (2012)
10.1021/TX9502047
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)
10.1021/mp100050d
Enabling the intestinal absorption of highly polar antiviral agents: ion-pair facilitated membrane permeation of zanamivir heptyl ester and guanidino oseltamivir.
J. Miller (2010)
10.1128/AAC.00555-08
Surveillance for Neuraminidase Inhibitor Resistance among Human Influenza A and B Viruses Circulating Worldwide from 2004 to 2008
Tiffany G. Sheu (2008)
10.1039/c0ob01117g
Prodrug design for the potent cardiovascular agent Nω-hydroxy-L-arginine (NOHA): synthetic approaches and physicochemical characterization.
D. Schade (2011)
10.1056/NEJMoa0903810
Emergence of a novel swine-origin influenza A (H1N1) virus in humans.
Fatimah S. Dawood (2009)
Hydroxylamine base was set free from its hydrochloride salt with sodium ethanolate
R Steudel (1975)
10.1021/JM980162U
Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors.
C. U. Kim (1998)
10.1093/JAC/42.5.647
In-vitro antimicrobial activity of HMR 3004 (RU 64004) against erythromycin A-sensitive and -resistant Corynebacterium spp. isolated from clinical specimens.
F. Soriano (1998)
10.1038/nrd2175
Antiviral agents active against influenza A viruses
E. De Clercq (2006)
10.1002/jcc.20084
UCSF Chimera—A visualization system for exploratory research and analysis
E. F. Pettersen (2004)
10.1002/CHIN.199714079
S‐2‐Naphthylmethyl Thioacetimidate Hydrobromide: A New Odorless Reagent for the Mild Synthesis of Substituted Acetamidines.
B. G. Shearer (1997)
10.4155/fmc.10.292
Novel neuraminidase inhibitors: identification, biological evaluation and investigations of the binding mode.
J. Kirchmair (2011)
10.1093/jac/dkq015
Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations
B. Davies (2010)
10.2165/00003088-199937060-00003
Clinical Pharmacokinetics of the Prodrug Oseltamivir and its Active Metabolite Ro 64-0802
G. He (1999)
10.1002/cmdc.201200155
Recent Advances in Neuraminidase Inhibitor Development as Anti‐influenza Drugs
E. Feng (2012)
10.1128/AAC.01311-09
Laninamivir Prodrug CS-8958, a Long-Acting Neuraminidase Inhibitor, Shows Superior Anti-Influenza Virus Activity after a Single Administration
Shuku Kubo (2010)
10.1006/JMBI.1996.0897
Development and validation of a genetic algorithm for flexible docking.
G. Jones (1997)
10.1126/SCIENCE.1090350
Are We Ready for Pandemic Influenza?
R. Webby (2003)
10.1056/NEJMp0910479
The Emergency Use Authorization of peramivir for treatment of 2009 H1N1 influenza.
D. Birnkrant (2009)
A simple method of estimating fifty percent endpoints
L. Reed (1938)
10.1016/S1368-7646(98)80038-1
Influenza virus resistance to neuraminidase inhibitors.
D. Mendel (1998)
10.3851/IMP1688
Laninamivir and its Prodrug, CS-8958: Long-Acting Neuraminidase Inhibitors for the Treatment of Influenza
M. Yamashita (2010)
10.1016/S0166-0934(01)00305-6
A rapid assay for evaluation of antiviral activity against coxsackie virus B3, influenza virus A, and herpes simplex virus type 1.
M. Schmidtke (2001)
10.1056/NEJMoa1304459
Human infection with a novel avian-origin influenza A (H7N9) virus.
Rongbao Gao (2013)
10.1016/j.bmc.2011.06.080
Intramolecular ion-pair prodrugs of zanamivir and guanidino-oseltamivir.
K. Liu (2011)
10.1038/nature08182
Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic
G. Smith (2009)
10.1021/mp300564v
Increasing oral absorption of polar neuraminidase inhibitors: a prodrug transporter approach applied to oseltamivir analogue.
D. Gupta (2013)



This paper is referenced by
10.1039/c9nj04909f
QSAR study of N-substituted Oseltamivir derivatives as potent avian influenza virus H5N1 inhibitors using quantum chemical descriptors and statistical methods
Samir Chtita (2020)
10.1007/7355_2014_84
Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies
T. Steinmetzer (2014)
10.23939/chcht13.04.417
Amidoxime-Functionalized (9,10-Dioxoantracen-1-yl)hydrazones
M. Stasevych (2019)
10.1016/j.carres.2019.01.008
Synthesis of neuraminidase-resistant sialoside-modified three-way junction DNA and its binding ability to various influenza viruses.
Miyuki Yamabe (2019)
10.1021/acsomega.9b01421
Discovery and SAR Research for Antivirus Activity of Novel Butenolide on Influenza A Virus H1N1 In Vitro and In Vivo
Zhen-ya Wang (2019)
10.1016/j.ejmech.2020.112423
Discovery of a non-zwitterionic oseltamivir analogue as a potent influenza a neuraminidase inhibitor.
H. Zhang (2020)
10.1002/MACP.201400525
Tailor-Made Antimicrobial/Antiviral Star Polymer via ATRP of Cyclodextrin and Guanidine-Based Macromonomer
Yuanfeng Pan (2015)
10.1021/acs.orglett.5b02798
Stereoselective Construction of Bridged trans-aza-Bicyclo[7/6,3/2,1]alkenyl Imines through Ring Expansion aza-Cope Rearrangement.
Mei-Hua Shen (2015)
10.1016/j.ejmech.2015.02.029
Structure-activity relationships of 3-O-β-chacotriosyl ursolic acid derivatives as novel H5N1 entry inhibitors.
Gaopeng Song (2015)
10.1002/adsc.201901054
The C=C Bond Decomposition Initiated by Enamine‐Azide Cycloaddition for Catalyst‐ and Additive‐Free Synthesis of N‐Sulfonyl Amidines
X. Zheng (2019)
10.1039/C8RA08207C
A convenient one-pot synthesis of N-substituted amidoximes and their application toward 1,2,4-oxadiazol-5-ones
Wong Phakhodee (2018)
10.1016/j.apsb.2015.07.006
New small-molecule drug design strategies for fighting resistant influenza A
Z. Shen (2015)
10.1039/c7cc07364j
Interception of amide ylides with sulfonamides: synthesis of (E)-N-sulfonyl amidines catalyzed by Zn(OTf)2.
J. Chen (2017)
10.1021/ol500522d
Aminative umpolung synthesis of aryl vicinal diamines from aromatic aldehydes.
X. Liu (2014)
10.2217/FVL.14.97
Complementary assays helping to overcome challenges for identifying neuraminidase inhibitors
Martina Richter (2015)
10.1016/j.drudis.2020.06.004
Oseltamivir analogs with potent anti-influenza virus activity.
S. Kumar (2020)
10.1016/J.TET.2017.07.062
Recent advances in the transformations of cycloalkane-fused oxiranes and aziridines
Melinda Nonn (2017)
10.1016/j.xphs.2020.01.028
A Novel Systematic Approach for Selection of Prodrugs Designed to Improve Oral Absorption.
Mai Shimizu (2020)
10.1016/J.TET.2015.12.017
Substrate-dependent fluorinations of highly functionalized cycloalkanes
L. Kiss (2016)
10.1021/jm500892k
Discovery of N-substituted oseltamivir derivatives as potent and selective inhibitors of H5N1 influenza neuraminidase.
Y. Xie (2014)
10.1038/srep27156
Discovery of prenylated flavonoids with dual activity against influenza virus and Streptococcus pneumoniae
U. Grienke (2016)
10.1007/s11094-016-1453-7
Using Bioisosteric Replacements to Enhance the Analgesic Properties of 4-Hydroxy-6,7-Dimethoxy-2-oxo-1,2-Dihydroquinoline-3-Carboxamides
I. Ukrainets (2016)
10.1002/CJOC.201500738
Design, Synthesis, and Evaluation of 3‐((4‐(t‐Butyl)‐2‐(2‐benzylidenehydrazinyl)thiazol‐5‐yl)methyl)quinolin‐2(1H)‐ones as Neuraminidase Inhibitors
Fang Yi-lin (2016)
10.1016/j.jviromet.2016.09.014
Platform for determining the inhibition profile of neuraminidase inhibitors in an influenza virus N1 background.
A. Hoffmann (2016)
10.1002/cmdc.201500103
Novel Furin Inhibitors with Potent Anti‐infectious Activity
Kornelia Hardes (2015)
10.1039/c9cc09869k
Electrochemically generated N-iodoaminium species as key intermediates for selective methyl sulphonylimination of tertiary amines.
B. Huang (2020)
10.1002/slct.202000675
Synthetic Advancement of Neuraminidase Inhibitor “Tamiflu”
Bhagirath Limbani (2020)
10.3389/fmicb.2017.00205
Discovery and Characterization of Diazenylaryl Sulfonic Acids as Inhibitors of Viral and Bacterial Neuraminidases
A. Hoffmann (2017)
10.1016/j.bmc.2017.06.025
Structure-activity relationships of 3-O-β-chacotriosyl oleanic acid derivatives as entry inhibitors for highly pathogenic H5N1 influenza virus.
S. Li (2017)
10.1016/j.ejmech.2016.04.061
Structure-activity relationships of 3-O-β-chacotriosyl oleanane-type triterpenoids as potential H5N1 entry inhibitors.
Gao-peng Song (2016)
10.1111/cbdd.13060
The hydrophobic side chain of oseltamivir influences type A subtype selectivity of neuraminidase inhibitors
X. Lin (2018)
10.3762/bjoc.13.233
Fluorination of some highly functionalized cycloalkanes: chemoselectivity and substrate dependence
A. Remete (2017)
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