Summers J B, Gunn B P, Mazdiyasni H, Goetze A M, Young P R, Bouska J B, Dyer R D, Brooks D W, Carter G W
Department 47K, Abbott Laboratories, Abbott Park, Illinois 60064.
J Med Chem. 1987 Nov;30(11):2121-6. doi: 10.1021/jm00394a032.
The hydroxamic acid functionally can be incorporated into simple molecules to produce potent inhibitors of 5-lipoxygenase. The ability of many of these hydroxamates to inhibit leukotriene synthesis in vivo has been measured directly with a rat peritoneal anaphylaxis model. Despite their potent enzyme inhibitory activity in vitro, many orally dosed hydroxamic acids only weakly inhibited leukotriene synthesis in vivo. This discrepancy is attributable at least in part to the rapid metabolism of hydroxamates to the corresponding carboxylic acids, which are inactive against the enzyme. A study of the structural features that affect this metabolism revealed that 2-arylpropionohydroxamic acids are relatively resistant to metabolic hydrolysis. Several members of this class of hydroxamates are described that are orally active inhibitors of leukotriene synthesis.
异羟肟酸在功能上可并入简单分子中以产生5-脂氧合酶的强效抑制剂。其中许多异羟肟酸在体内抑制白三烯合成的能力已通过大鼠腹膜过敏反应模型直接测定。尽管它们在体外具有强大的酶抑制活性，但许多口服给药的异羟肟酸在体内仅微弱地抑制白三烯合成。这种差异至少部分归因于异羟肟酸迅速代谢为相应的羧酸，而这些羧酸对该酶无活性。一项关于影响这种代谢的结构特征的研究表明，2-芳基丙酰异羟肟酸相对抗代谢水解。描述了这类异羟肟酸的几个成员，它们是白三烯合成的口服活性抑制剂。
