Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza virus sialidases. 1. Discovery, synthesis, biological activity, and structure-activity relationships of 4-guanidino- and 4-amino-4H-pyran-6-carboxamides

J Med Chem. 1998 Mar 12;41(6):787-97. doi: 10.1021/jm970374b.

Abstract

4-Amino- and 4-guanidino-4H-pyran-6-carboxamides 4 and 5 related to zanamivir (GG167) are a new class of inhibitors of influenza virus sialidases. Structure--activity studies reveal that, in general, secondary amides are weak inhibitors of both influenza A and B viral sialidases. However, tertiary amides, which contain one or more small alkyl groups, show much greater inhibitory activity, particularly against the influenza A virus enzyme. The sialidase inhibitory activities of these compounds correlate well with their in vitro antiviral efficacy, and several of the most potent analogues displayed useful antiviral activity in vivo when evaluated in a mouse model of influenza A virus infection. Carboxamides which were highly active sialidase inhibitors in vitro also showed good antiviral activity in the mouse efficacy model of influenza A infection when administered intranasally but displayed modest activity when delivered by the intraperitoneal route.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Intranasal
  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Guanidines / chemical synthesis
  • Guanidines / chemistry
  • Guanidines / pharmacokinetics
  • Guanidines / pharmacology*
  • Influenza A virus / drug effects*
  • Influenza A virus / enzymology
  • Influenza B virus / drug effects*
  • Influenza B virus / enzymology
  • Injections, Intraperitoneal
  • Mice
  • Neuraminidase / antagonists & inhibitors*
  • Orthomyxoviridae Infections / drug therapy
  • Orthomyxoviridae Infections / enzymology
  • Pyrans / chemical synthesis
  • Pyrans / chemistry
  • Pyrans / pharmacokinetics
  • Pyrans / pharmacology*
  • Sialic Acids / chemistry
  • Sialic Acids / pharmacokinetics
  • Sialic Acids / pharmacology*
  • Structure-Activity Relationship
  • Zanamivir

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Guanidines
  • Pyrans
  • Sialic Acids
  • Neuraminidase
  • Zanamivir