title: Zanamivir Amidoxime- and N-Hydroxyguanidine-Based Prodrug Approaches to Tackle Poor Oral Bioavailability.
abstract: 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.
authors.affiliation: Christian-Albrechts University of Kiel, Pharmaceutical Institute, Department of Pharmaceutical Chemistry, Kiel, 24118, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Schade
authors.affiliation: Christian-Albrechts University of Kiel, Pharmaceutical Institute, Department of Pharmaceutical Chemistry, Kiel, 24118, Germany.
authors.forename: Jürke
authors.initials: J
authors.lastname: Kotthaus
authors.affiliation: Christian-Albrechts University of Kiel, Pharmaceutical Institute, Department of Pharmaceutical Chemistry, Kiel, 24118, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Riebling
authors.affiliation: Christian-Albrechts University of Kiel, Pharmaceutical Institute, Department of Pharmaceutical Chemistry, Kiel, 24118, Germany.
authors.forename: Joscha
authors.initials: J
authors.lastname: Kotthaus
authors.affiliation: University of Lübeck, Institute of Experimental & Clinical Pharmacology & Toxicology, Lübeck, 23538, Germany.
authors.forename: Helge
authors.initials: H
authors.lastname: Müller-Fielitz
authors.affiliation: University of Lübeck, Institute of Experimental & Clinical Pharmacology & Toxicology, Lübeck, 23538, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Raasch
authors.affiliation: Friedrich Schiller University, Institute of Virology and Antiviral Therapy, Jena, 07745, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Hoffmann
authors.affiliation: Friedrich Schiller University, Institute of Virology and Antiviral Therapy, Jena, 07745, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schmidtke
authors.affiliation: Christian-Albrechts University of Kiel, Pharmaceutical Institute, Department of Pharmaceutical Chemistry, Kiel, 24118, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Clement
mesh_terms: D000284:Administration, Oral; D000578:Amidines / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D004285:Dogs; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D006146:Guanidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D006898:Hydroxylamines; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects; D061985:Madin Darby Canine Kidney Cells; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D053243:Zanamivir / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000578:Amidines; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D006898:Hydroxylamines; D011355:Prodrugs; C029604:hydroxyguanidine; D009439:Neuraminidase; D053243:Zanamivir; C023731:acetamidine
keywords: bioavailability; drug-like properties; guanidine bioisoster; amidine; influenza A; neuraminidase inhibitor; pharmacokinetics; prodrug; synthesis