title: KF24345, an adenosine uptake inhibitor, ameliorates the severity and mortality of lethal acute pancreatitis via endogenous adenosine in mice.
abstract: Adenosine protects against cellular damage and dysfunction under several adverse conditions including inflammation and ischemia. In this study, we examined the effects of 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione hydrochloride (KF24345), an adenosine uptake inhibitor, on experimental acute pancreatitis induced by choline-deficient and ethionine-supplemented diet in mice. KF24345, administered with the diet onset and every 24 h thereafter, prevented hyperamylasemia, acinar cell injury and serum tumor necrosis factor-alpha elevation and ultimately decreased mortality. Therapeutic treatment with KF24345, which started 32 h after the diet onset, also decreased mortality. The beneficial effect of KF24345 on mortality was abolished by the pretreatment with 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385), a selective adenosine A(2A) receptor antagonist. An intravenous injection of KF24345 at 48 h after the diet onset increased plasma adenosine concentrations in mice with acute pancreatitis. These results suggest that KF24345 shows anti-pancreatitis effects via endogenous adenosine and adenosine A(2A) receptors. The adenosine uptake inhibition could be a new therapeutic approach for acute pancreatitis.
authors.affiliation: Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company, Limited, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan. tohru.noji@kyowa.co.jp
authors.forename: Tohru
authors.initials: T
authors.lastname: Noji
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Nan-ya
authors.forename: Mirai
authors.initials: M
authors.lastname: Mizutani
authors.forename: Chikako
authors.initials: C
authors.lastname: Katagiri
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sano
authors.forename: Chie
authors.initials: C
authors.lastname: Takada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Akira
authors.initials: A
authors.lastname: Karasawa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kusaka
mesh_terms: D000208:Acute Disease; D000241:Adenosine / Q000037:antagonists & inhibitors* / Q000097:blood; D000681:Amylases / Q000097:blood; D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D004032:Diet; D005260:Female; D007770:L-Lactate Dehydrogenase / Q000097:blood; D051379:Mice; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009929:Organ Size; D010179:Pancreas / Q000187:drug effects; D010195:Pancreatitis / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D011744:Pyrimidinones / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C444645:3-(1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl)-1,6-dimethyl-2,4-(1H,3H)-quinazolinedione; D014179:Neurotransmitter Uptake Inhibitors; D011744:Pyrimidinones; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D007770:L-Lactate Dehydrogenase; D000681:Amylases; D000241:Adenosine