Development of Novel Potent Orally Bioavailable Oseltamivir Derivatives Active against Resistant Influenza A

Schade, Dennis; Kotthaus, Joscha; Riebling, Lukas; Kotthaus, Jürke; Müller-Fielitz, Helge; Raasch, Walter; Koch, Oliver; Seidel, Nora; Schmidtke, Michaela; Clement, Bernd

doi:10.1021/jm401492x

Cited by 77 publications

(62 citation statements)

References 44 publications

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“…[14,56,57] Moreover,a lthough excellent amidine prodrugs have been developed, [58] there is no or only little progress in the design of guanidine prodrugs. [59] Therefore, it will likely be difficult to convert theset etrabasic inhibitors into completely neutral analogues on the basis of only prodrug strategies. All potent low-nanomolar furin inhibitors presently known possesss everal basic residues, and such compounds will be scarcely orally available.…”

Section: Discussionmentioning

confidence: 99%

Novel Furin Inhibitors with Potent Anti‐infectious Activity

et al. 2015

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New peptidomimetic furin inhibitors with unnatural amino acid residues in the P3 position were synthesized. The most potent compound 4-guanidinomethyl-phenylacteyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148) inhibits furin with a Ki value of 5.5 pM. The derivatives also strongly inhibit PC1/3, whereas PC2 is less affected. Selected inhibitors were tested in cell culture for antibacterial and antiviral activity against infectious agents known to be dependent on furin activity. A significant protective effect against anthrax and diphtheria toxin was observed in the presence of the furin inhibitors. Furthermore, the spread of the highly pathogenic H5N1 and H7N1 avian influenza viruses and propagation of canine distemper virus was strongly inhibited. Inhibitor MI-1148 was crystallized in complex with human furin. Its N-terminal guanidinomethyl group in the para position of the P5 phenyl ring occupies the same position as that found previously for a structurally related inhibitor containing this substitution in the meta position, thereby maintaining all of the important P5 interactions. Our results confirm that the inhibition of furin is a promising strategy for a short-term treatment of acute infectious diseases.

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Section: Discussionmentioning

confidence: 99%

Novel Furin Inhibitors with Potent Anti‐infectious Activity

et al. 2015

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“…H5N1 avian influenza A virus is the cause of significant morbidity among humans, posing a serious threat to public health due to its transmission from animals to human being [1,2]. The two common classes of antiviral drugs used to treat influenza are neuraminidase inhibitors, like zanamivir and oseltamivir, and inhibitors of the viral M2 protein, such as amantadine and rimantadine [3].…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationships of 3-O-β-chacotriosyl ursolic acid derivatives as novel H5N1 entry inhibitors

Song

Shen

et al. 2015

European Journal of Medicinal Chemistry

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“…Compound (18) exhibits subnanomolar affinity for various N1 and N2 NAs and retains acceptable affinity against the H274Y N1 variant (IC 50 ¼ 14.5 nM). For its N-hydroxy prodrug (19), an excellent oral bioavailability in rats (31%) was determined [21]. A few NAIs have been prepared based on the cyclopentane core, whereas most analogues suffered from relatively poor activity.…”

Section: Structure and Replication Of Influenza Virusesmentioning

confidence: 99%

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

Steinmetzer¹,

Hardes²,

Böttcher‐Friebertshäuser³

et al. 2014

Topics in Medicinal Chemistry

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Only four drugs are approved for the specific treatment of acute influenza infections worldwide. These drugs address either the viral neuraminidase or the M2-channel but suffer from poor efficacy and the rapid emergence of drug resistances. Some additional drugs are launched in few countries, but their efficacy is relatively low and often limited to certain influenza strains. Ideally, new drugs should possess a broad potency against all influenza viruses and be less susceptible to the development of resistances. The propagation cycle of the influenza virus offers many possibilities for the development of new anti-influenza drugs. Various compounds addressing viral targets reached clinical development, from which the most-advanced candidate is the polymerase inhibitor favipiravir. A promising strategy could be also the inhibition of host targets and signaling pathways, e.g., by already approved kinase inhibitors, anti-inflammatory drugs, or immunomodulatory agents. However, the benefit of these agents has to be demonstrated in controlled clinical trials. A broader arsenal of approved drugs will offer the possibility for more efficient combinatorial therapies in the future. The first proof of concept studies for such multiple drug therapies in infected mice revealed beneficial effects. Moreover, this strategy should reduce the rapid emergence of resistant influenza strains.

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Development of Novel Potent Orally Bioavailable Oseltamivir Derivatives Active against Resistant Influenza A

Cited by 77 publications

References 44 publications

Novel Furin Inhibitors with Potent Anti‐infectious Activity

Novel Furin Inhibitors with Potent Anti‐infectious Activity

Structure–activity relationships of 3-O-β-chacotriosyl ursolic acid derivatives as novel H5N1 entry inhibitors

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

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