N1-hydroxylated derivatives of chlorpropamide and its analogs as inhibitors of aldehyde dehydrogenase in vivo.
N1-hydroxylated derivatives of chlorpropamide and its analogs as inhibitors of aldehyde dehydrogenase in vivo.
复制标题
氯丙酰胺的 N1-羟基化衍生物及其类似物作为体内乙醛脱氢酶的抑制剂。
DOI：
10.1021/jm00098a007
复制
发表时间：
1992
影响因子：
7.3
通讯作者：
Nagasawa,HT
中科院分区：
文献类型：
--
作者：
Lee,MJ;Elberling,JA;Nagasawa,HT
Certain (arylsulfonyl) urea hypoglycemic drugs exemplified by chlorpropamide (CP) are known to interact pharmacologically with alcohol (ethanol) to elicit a chlorpropamide-alcohol flushing (CP AF) reaction that is reminiscent of the disulfiram-ethanol reaction (DER). In the present structure-activity study, designed to elucidate the mechanism of inhibition of aldehyde dehydrogenase (A1DH) by CP, we discovered that the A^-methoxy derivative of CP2a was a potent inhibitor of A1DH in vivo similar in activity to that of the A^-ethyl derivative 2b. Both 2a and 2b can release n-propyl isocyanate, a known inhibitor of A1DH, nonenzymatically. However,(arylsulfonyl) carbamates that are structurally analogous to 2a were also active inhibitors of A1DH, whereas the corresponding (arylsulfonyl) carbamate analogs of 2b were uniformly without activity. We propose a mechanism of bioactivation of 2a and its analogs that involves initial O-demethylation followed by disproportionation and solvolysis of the intermediate formed to release nitroxyl, the putative inhibitor of A1DH.Chlorpropamide (CP, 1), a sulfonylurea-type oral hypoglycemic agent, when taken in combination with alco-holic beverages even in moderate amounts, elicits an adverse physiological reaction manifested visibly by facial flushing in approximately 30% of individuals who use this drugto control blood sugar.* 1
