[Pharmacological study on the effects of the adenosine uptake inhibitor KF24345 on inflammatory diseases].
Adenosine protects against cellular damage and dysfunction under several adverse conditions, including inflammation. We examined the effects of KF24345, a novel adenosine uptake inhibitor, on inflammatory diseases to investigate whether the adenosine uptake inhibition is useful for the treatment of inflammation. KF24345 inhibited adenosine uptake into washed erythrocytes (in vitro) and sampled blood cells from mice after its oral administration (in vivo). KF24345 significantly suppressed lipopolysaccharide-induced tumor necrosis factor-alpha production and leukopenia in mice, and the effects of KF24345 were abolished by the treatment with a non-selective or an A(2A)-selective adenosine receptor antagonist. In the experimental glomerulonephritis induced in mice by anti-glomerular basement membrane antiserum, KF24345 significantly inhibited proteinuria and glomerular damage without exhibiting the side effects observed following the treatment with prednisolone and cyclophosphamide. In addition, KF24345 ameliorated the severity of experimental acute pancreatitis induced by cerulein or choline-deficient and ethionine-supplemented diet in mice, and it decreased mortality accompanying severe acute pancreatitis. The anti-pancreatitis effects of KF24345 were abolished by the treatment with a non-selective or an A(2A)-selective adenosine receptor antagonist. These results suggest that KF24345 and adenosine uptake inhibitors can be a new therapeutic approach for various inflammatory diseases, including glomerulonephritis and acute pancreatitis.
Noji
Tohru
T
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Sunto-gun, Japan.
Karasawa
Akira
A
Kusaka
Hideaki
H
D000208:Acute Disease; D000241:Adenosine / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D003864:Depression, Chemical; D004912:Erythrocytes / Q000378:metabolism; D005921:Glomerulonephritis / Q000188:drug therapy*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D007970:Leukopenia / Q000188:drug therapy; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D051379:Mice; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D010195:Pancreatitis / Q000188:drug therapy*; D011744:Pyrimidinones / Q000494:pharmacology* / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C444645:3-(1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl)-1,6-dimethyl-2,4-(1H,3H)-quinazolinedione; D008070:Lipopolysaccharides; D014179:Neurotransmitter Uptake Inhibitors; D011744:Pyrimidinones; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D000241:Adenosine