Rokach J, Girard Y, Hamel P, Reader G, Rooney C S, Mandel L R, Cragoe E J, Zacchei A G
J Med Chem. 1980 Jul;23(7):773-80. doi: 10.1021/jm00181a014.
A variety of substituent groups has been attached to the exocyclic imine function of 2-imino-3-methylthiazolidine (1) in a search for metabolic precursors of this potent inhibitor of the enzyme indoleethylamine N-methyltransferase (INMT) which would exhibit superior pharmacodynamic properties in animals. It has been determined that chemically stable derivatives of 1 based on succinic, nicotinic, and N-acylated amino acids, although they lack in vitro efficacy, are potent inhibitors of INMT when administered orally or intravenously to rabbits. Metabolic studies carried out with 14C-labeled N,N'-bix(3-methyl-2-thiazolidinylidene)succinamide (3) have established that conversion of this compound to 1 occurs both in the whole rabbit and in the isolated rabbit liver. 1 itself has been shown to be metabolically inert in rabbits, being excreted primarily in the urine.
为了寻找这种强效的吲哚乙胺N-甲基转移酶（INMT）抑制剂的代谢前体，使其在动物体内表现出更优异的药效学性质，人们已将多种取代基连接到2-亚氨基-3-甲基噻唑烷（1）的环外亚胺官能团上。现已确定，基于琥珀酸、烟酸和N-酰化氨基酸的1的化学稳定衍生物，尽管它们缺乏体外活性，但口服或静脉注射给兔子时是INMT的有效抑制剂。用14C标记的N,N'-双（3-甲基-2-噻唑烷叉基）琥珀酰胺（3）进行的代谢研究表明，该化合物在整个兔子体内和离体兔肝中均可转化为1。1本身在兔子体内已被证明代谢惰性，主要经尿液排泄。
