Anti-inflammatory activity of non-nucleoside adenosine deaminase inhibitor FR234938.
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.
Kuno
Masako
M
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. masako.kuno@jp.astellas.com
Seki
Nobuo
N
Tsujimoto
Susumu
S
Nakanishi
Isao
I
Kinoshita
Takayoshi
T
Nakamura
Katsuya
K
Terasaka
Tadashi
T
Nishio
Nobuya
N
Sato
Akihiro
A
Fujii
Takashi
T
D000241:Adenosine / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000235:genetics; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D024043:Collagen Type II / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology*; D016753:Interleukin-10 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009281:Naphthalenes / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D058892:Adenosine Deaminase Inhibitors; D000893:Anti-Inflammatory Agents; D024043:Collagen Type II; D004791:Enzyme Inhibitors; C510717:FR234938; D007093:Imidazoles; D008070:Lipopolysaccharides; D009281:Naphthalenes; D011720:Pyrazoles; D011725:Pyridines; D043683:Receptors, Adenosine A2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; D016753:Interleukin-10; C102861:FK 838; D000243:Adenosine Deaminase; D000241:Adenosine