Anti-inflammatory activity of non-nucleoside adenosine deaminase inhibitor FR234938

Eur J Pharmacol. 2006 Mar 18;534(1-3):241-9. doi: 10.1016/j.ejphar.2006.01.042. Epub 2006 Mar 3.

Abstract

Adenosine has anti-inflammatory activity. Adenosine deaminase (EC 3.5.4.4) metabolizes extracellular adenosine, resulting in an exacerbation of inflammation. Consequently, it was hypothesized that adenosine deaminase inhibitors produce anti-inflammatory activity by increasing extracellular adenosine concentration. This group recently developed a non-nucleoside adenosine deaminase inhibitor, FR234938, by using rational structure-based drug design. FR234938 inhibits recombinant human adenosine deaminase enzyme competitively. FR234938 inhibits interleukin (IL)-6-dependent immunoglobulin (Ig) M production by SKW6.4 cells, in the presence of adenosine. Inhibitory effect of FR234938/adenosine combination is blocked by an A2a adenosine receptor antagonist. FR234938 also inhibits anti-type II collagen delayed type hypersensitivity (DTH) in a dose-dependent manner, both in the presence and absence of recombinant human adenosine deaminase. Moreover, FR234938 inhibits tumor necrosis factor (TNF)-alpha and IL-10 production in a lipopolysaccharide (LPS)-induced cytokine production model in mice. These results indicate that FR234938 has potential anti-inflammatory activity. Non-nucleoside adenosine deaminase inhibitor FR234938 has good potential as a new type of anti-rheumatic and anti-inflammatory drug, by modulating host-defense concentrations of adenosine.

MeSH terms

  • Adenosine / pharmacology
  • Adenosine Deaminase / genetics
  • Adenosine Deaminase Inhibitors*
  • Animals
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology*
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • Cell Line
  • Collagen Type II / immunology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hypersensitivity, Delayed / immunology
  • Hypersensitivity, Delayed / prevention & control
  • Imidazoles / pharmacology*
  • Interleukin-10 / blood
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Models, Animal
  • Naphthalenes / pharmacology*
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Receptors, Adenosine A2 / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Adenosine Deaminase Inhibitors
  • Anti-Inflammatory Agents
  • Collagen Type II
  • Enzyme Inhibitors
  • FR234938
  • Imidazoles
  • Lipopolysaccharides
  • Naphthalenes
  • Pyrazoles
  • Pyridines
  • Receptors, Adenosine A2
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • lipopolysaccharide, Escherichia coli O111 B4
  • Interleukin-10
  • FK 838
  • Adenosine Deaminase
  • Adenosine