Antiallergy activity of Sch 37224, a new inhibitor of leukotriene formation.

Abstract

Sulfidopeptide leukotrienes (LTs) C4, D4 and E4 are important mediators in the pathophysiology of bronchial asthma. Sch 37224, 1-(1,2-dihydro-4-hydroxy-2-oxo-1-phenyl-1,8-naphthyridin-3-yl) pyrrolidinium, hydroxide inner salt, has been found to inhibit the formation of these autocoids. Although Sch 37224 did not inhibit 5-lipoxygenase, cyclooxygenase or phospholipase A2, it inhibited LTD4 and thromboxane B2 release by anaphylactic guinea pig lung (IC40 = 3.9 and 1.9 microM, respectively). At 5 microM Sch 37224 also inhibited superoxide anion radical generation from activated human polymorphonuclear neutrophilic leukocytes. When administered p.o. to guinea pigs, Sch 37224 decreased a LT-mediated allergic bronchospasm (ED40 = 1.1 mg/kg) for 6 hr and did not exhibit tolerance. In addition to its activities in allergen-induced bronchospasm in guinea pigs, Sch 37224 also inhibited hyperventilation-induced bronchospasm in guinea pigs at 0.5 to 5 mg/kg and anaphylactic bronchospasm in rats at 0.1 to 10 mg/kg. Sch 37224 was weak or ineffective as an antagonist of histamine, methacholine, serotonin, LTC4 or platelet activating factor induced bronchospasms in guinea pigs. Also, Sch 37224 was not a bronchodilator or calcium influx blocker and had only weak relaxant activity on guinea pig trachea in vitro (IC40 = 51 microM). Sch 37224 is, therefore, a potential antiallergic agent that inhibits LT release. It is p.o. effective in animal models of allergic and nonallergic-mediated bronchospasms.

• Authors: W Kreutner, J Sherwood, S Sehring, C Rizzo, R W Chapman, M I Siegel, R W Egan
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 247 Issue 3 Pg. 997-1003 (Dec 1988) ISSN: 0022-3565 [Print] United States
• PMID: 2462630 (Publication Type: Journal Article)

Chemical References

• Arachidonic Acids
• Histamine H1 Antagonists
• Leukotriene Antagonists
• Leukotrienes
• Naphthyridines
• Sch 37224
• Arachidonic Acid
• Thromboxane B2

Topics

• Animals
• Arachidonic Acid
• Arachidonic Acids (metabolism)
• Bronchi (drug effects)
• Bronchial Spasm (prevention & control)
• Guinea Pigs
• Histamine H1 Antagonists (pharmacology)
• Histamine Release (drug effects)
• Hypersensitivity (drug therapy)
• In Vitro Techniques
• Leukotriene Antagonists
• Leukotrienes (biosynthesis)
• Male
• Naphthyridines (pharmacology)
• Rats
• Thromboxane B2 (metabolism)