Ohemeng K A, Nguyen V N, Schwender C F, Singer M, Steber M, Ansell J, Hageman W
R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869.
Bioorg Med Chem. 1994 Mar;2(3):187-93. doi: 10.1016/s0968-0896(00)82014-3.
Two series of novel bishydroxamic acids 2 and 3 (types A and B) were synthesized and tested for inhibition of 5-lipoxygenase from rat basophile leukemia (RBL) cells. Both series were potent inhibitors of the isolated enzyme but only the type B reverse hydroxamic acids possessed significant oral activity. The most potent compound, orally, was 3a, [IC50 = 270 nM; ED50 = 1.86 mg/kg], which compares favorably with the clinically useful 5-lipoxygenase inhibitor, zileuton. Unlike known hydroxamic acid inhibitors, the oral activity in this series appears to be associated with the second hydroxamic acid group. The corresponding monohydroxamic acids retained inhibitor potency, in vitro, with reduced oral activity in a mouse zymosan peritonitis model. Compound 4e [IC50 = 7 nM], a monohydroxamic acid derivative related to 3a, is among the most potent inhibitors of the isolated enzyme yet to be reported.
合成了两个系列的新型双异羟肟酸2和3（A类和B类），并测试了它们对大鼠嗜碱性粒细胞白血病（RBL）细胞中5-脂氧合酶的抑制作用。两个系列都是分离酶的有效抑制剂，但只有B类反向异羟肟酸具有显著的口服活性。口服活性最强的化合物是3a，[IC50 = 270 nM；ED50 = 1.86 mg/kg]，与临床有用的5-脂氧合酶抑制剂齐留通相比具有优势。与已知的异羟肟酸抑制剂不同，该系列中的口服活性似乎与第二个异羟肟酸基团有关。相应的单异羟肟酸在体外保留了抑制活性，但在小鼠酵母聚糖腹膜炎模型中的口服活性降低。化合物4e [IC50 = 7 nM]，一种与3a相关的单异羟肟酸衍生物，是迄今报道的分离酶最有效的抑制剂之一。
