(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

Abstract

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 LTC₄ and LTB₄ (LT-synthesizing enzymes); cytosolic phospholipase A₂ (cPLA₂), 5-lipoxygenase (5-LO), leukotriene (LT)C₄ synthase and LTA₄ hydrolase. AS-35 dose-dependently inhibited IgE- and A23187-stimulated production of LTC₄ by up to 71.5–84.8% and that of LTB₄ by 48.3–49.2% at 2.5×10⁻⁵ M. The assays for cPLA₂⁻, 5-LO-, LTC₄ synthase- and LTA₄ hydrolase-activities revealed that the inhibition is attributable to suppression of cPLA₂, 5-LO and LTC₄ synthase but not LTA₄ hydrolase. We have also studied the action of AS-35 on the release of β-hexosaminidase (β-HEX) as a marker of preformed mediators. AS-35 had only weak inhibitory action on the release of β-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 LTC₄ synthesis.