Sherlock M H, Kaminski J J, Tom W C, Lee J F, Wong S C, Kreutner W, Bryant R W, McPhail A T
Pharmaceutical Research Division, Schering-Plough Corporation, Bloomfield, New Jersey 07003.
J Med Chem. 1988 Nov;31(11):2108-21. doi: 10.1021/jm00119a010.
A novel class of antiallergy agents, the substituted 1,8-naphthyridin-2(1H)-ones, is described. The present compounds are orally active, potent inhibitors of allergic and nonallergic bronchospasm in animal models. Structure-activity studies of the lead compound in this series, 1-phenyl-3-n-butyl-4-hydroxynaphthyridin-2(1H)-one (11), identified three compounds of interest, 1-phenyl-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H)-one (12), 1-(3'-chlorophenyl)-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H )-one (87), and 1-(3'-methoxyphenyl)-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1 H)-one (89). The mechanism of antiallergy activity may involve inhibition of the release of the sulfidopeptide leukotrienes. 1-Phenyl-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H)-one, Sch 33303 (12), was selected for preclinical development as an antiallergy agent.
描述了一类新型抗过敏剂，即取代的1,8 - 萘啶 - 2(1H)-酮。本化合物具有口服活性，是动物模型中过敏性和非过敏性支气管痉挛的有效抑制剂。对该系列先导化合物1 - 苯基 - 3 - 正丁基 - 4 - 羟基萘啶 - 2(1H)-酮（11）进行构效关系研究，确定了三种有意义的化合物，即1 - 苯基 - 3 - (2 - 丙烯基)-4 - 乙酰氧基 - 1,8 - 萘啶 - 2(1H)-酮（12）、1 - (3'-氯苯基)-3 - (2 - 丙烯基)-4 - 乙酰氧基 - 1,8 - 萘啶 - 2(1H)-酮（87）和1 - (3'-甲氧基苯基)-3 - (2 - 丙烯基)-4 - 乙酰氧基 - 1,8 - 萘啶 - 2(1H)-酮（89）。抗过敏活性机制可能涉及抑制硫肽白三烯的释放。1 - 苯基 - 3 - (2 - 丙烯基)-4 - 乙酰氧基 - 1,8 - 萘啶 - 2(1H)-酮，Sch 33303（12），被选为抗过敏剂进行临床前开发。
