(9-[4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido [1,2-a] pyrimidin-4-one), AS-35, inhibits leukotriene synthesis.
AS-35, (9-[4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1, 2-a] pyrimidin-4-one), was developed as a leukotriene (LT) receptor antagonist, which also inhibited IgE-mediated release of leukotrienes (LTs). We have investigated the action of AS-35 on the enzyme activities which are involved in the synthesis of LTC(4) and LTB(4) (LT-synthesizing enzymes); cytosolic phospholipase A(2) (cPLA(2)), 5-lipoxygenase (5-LO), leukotriene (LT)C(4) synthase and LTA(4) hydrolase. AS-35 dose-dependently inhibited IgE- and A23187-stimulated production of LTC(4) by up to 71.5-84.8% and that of LTB(4) by 48.3-49.2% at 2. 5x10(-5) M. The assays for cPLA(2)(-), 5-LO-, LTC(4) synthase- and LTA(4) hydrolase-activities revealed that the inhibition is attributable to suppression of cPLA(2), 5-LO and LTC(4) synthase but not LTA(4) hydrolase. We have also studied the action of AS-35 on the release of beta-hexosaminidase (beta-HEX) as a marker of preformed mediators. AS-35 had only weak inhibitory action on the release of beta-HEX. The results indicate that anti-allergic action of AS-35 is predominantly attributable to its inhibition of LT synthesis by suppressing three consecutive enzymes for LTC(4) synthesis.
Hamasaki
Y
Y
Saga Medical School, Department of Pediatrics, 5-1-1 Nabeshima, Saga, Japan. hamasaki@post.saga-med.ac.jp
Zaitu
M
M
Tsuji
K
K
Miyazaki
M
M
Hayasaki
R
R
Muro
E
E
Yamamoto
S
S
Kobayashi
I
I
Matsuo
M
M
Ichimaru
T
T
Miyazaki
S
S
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002474:Cell-Free System; D003600:Cytosol / Q000201:enzymology; D017572:Leukotriene A4 / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D017997:Leukotriene C4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D010741:Phospholipases A / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D013379:Substrate Specificity; D013777:Tetrazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D017572:Leukotriene A4; D020024:Leukotriene Antagonists; D011725:Pyridines; D011744:Pyrimidinones; D013777:Tetrazoles; C073308:AS 35; D007975:Leukotriene B4; D016718:Arachidonic Acid; D017997:Leukotriene C4; D010741:Phospholipases A; D001619:beta-N-Acetylhexosaminidases