Antiallergy activity of Sch 37224, a new inhibitor of leukotriene formation.
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.
Kreutner
W
W
Department of Allergy, Schering-Plough Corporation, Bloomfield, New Jersey.
Sherwood
J
J
Sehring
S
S
Rizzo
C
C
Chapman
R W
RW
Siegel
M I
MI
Egan
R W
RW
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects; D001986:Bronchial Spasm / Q000517:prevention & control; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D006967:Hypersensitivity / Q000188:drug therapy*; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000096:biosynthesis; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology*; D051381:Rats; D013929:Thromboxane B2 / Q000378:metabolism
D001095:Arachidonic Acids; D006634:Histamine H1 Antagonists; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D009287:Naphthyridines; C058078:Sch 37224; D016718:Arachidonic Acid; D013929:Thromboxane B2