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

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.

• Authors: Masako Kuno, Nobuo Seki, Susumu Tsujimoto, Isao Nakanishi, Takayoshi Kinoshita, Katsuya Nakamura, Tadashi Terasaka, Nobuya Nishio, Akihiro Sato, Takashi Fujii
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 534 Issue 1-3 Pg. 241-9 (Mar 18 2006) ISSN: 0014-2999 [Print] Netherlands
• PMID: 16515782 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• Adenosine (pharmacology)
• Adenosine Deaminase (genetics)
• Adenosine Deaminase Inhibitors
• Animals
• Anti-Inflammatory Agents (pharmacokinetics, pharmacology)
• B-Lymphocytes (drug effects, metabolism)
• Cell Line
• Collagen Type II (immunology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacokinetics, pharmacology)
• Humans
• Hypersensitivity, Delayed (immunology, 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)