Cyclic amidine inhibitors of indolamine N-methyltransferase.
Cyclic amidine inhibitors of indolamine N-methyltransferase.
复制标题
吲哚胺 N-甲基转移酶的环状脒抑制剂。
DOI：
10.1021/jm00189a004
复制
发表时间：
1979
影响因子：
7.3
通讯作者：
L. R. Mandel
中科院分区：
文献类型：
--
作者：
J. Rokach;P. Hamel;N. R. Hunter;G. Reader;C. Rooney;P. Anderson;E. Cragoe;L. R. Mandel
报道了大量与2，3，4，6，7，8，-六氢吡咯并[1，2-a]嘧啶(DBN)相关的单环和双环以及少数三环、酰胺类化合物的合成。本文报道了体外抑制兔和人肺的吲哚胺N-甲基转移酶(INMT)的效力。在体外实验中，发现4个双环酰胺类化合物和11个单环类化合物的体外效价与DBN相当或更好。对于双环胺，增加环的尺寸或引入取代基会降低活性。在单环类似物中，最有效的代表是具有外环亚氨基的五元或六元体系，并在内环氮上结合甲基或乙基取代基。加成取代基的引入降低了抑制活性。2，3，5，6-Tetrahydro-8H-imidazo[2，1-c][1，4]thiazine和3-甲基-2-亚氨基噻唑烷经口给药后对兔肺组织的抑制作用已被证明。
Syntheses of a large number of mono- and bicyclic, as well as a few tricyclic, amidine derivatives related to 2,3,4,6,7,8,-hexahydropyrrolo[1,2-a]pyrimidine (DBN) are reported. In vitro potencies for inhibition of the enzyme indolamine N-methyltransferase (INMT) from rabbit and human lung are presented. Four bicyclic amidine derivatives and 11 monocyclic derivatives were found to be equal or superior to DBN in in vitro potencies. With the bicyclic amidines, increasing ring size or introduction of substituents reduced activity. Among the monocyclic analogues, the most potent representatives were five- or six-membered systems with an exocyclic imino group, combined with methyl of ethyl substituents on the endocyclic nitrogen. Introduction of additonal substituents decreased inhibitory potency. 2,3,5,6-Tetrahydro-8H-imidazo[2,1-c][1,4]thiazine and 3-methyl-2-iminothiazolidine have been shown to cause inhibition of lung INMT when administered orally to rabbits.