Saito M, Hashimoto M, Kawaguchi N, Shibata H, Fukami H, Tanaka T, Higuchi N
Bio-organic Chemistry Laboratory, Institute for Fundamental Research, Suntory Research Center, Osaka, Japan.
J Enzyme Inhib. 1991;5(1):51-75. doi: 10.3109/14756369109069060.
Several pyrrolidine derivatives have been synthesized and examined for their inhibitory activity on post-proline cleaving enzymes from Flavobacterium meningosepticum and bovine brain. Almost all the compounds tested in this study inhibited the activity of both enzymes at low IC50 values (from nM to microM) but a specificity difference was observed with alkylacyl-peptidyl-pyrrolidine derivatives which strongly inhibited only the bacterial enzyme. The most effective inhibitors have a proline residue on their P2 sites and a substituted or unsubstituted phenoxybutyryl moiety on their P3 sites. Thus phenoxybutyryl-prolyl-pyrrolidine is the most effective partial structure of the inhibitors. The best inhibitors found were: 4-(4-benzylphenoxy)butyryl-prolyl-pyrrolidine for bacterial enzyme (IC50 1.4 nM) and 4-phenylbutyryl-thioprolyl-pyrrolidine for bovine brain enzyme (IC50 67 nM). In the passive avoidance test, using amnesic rats experimentally induced with scopolamine, the pyrrolidine derivatives which had potent inhibitory activity toward post-proline cleaving enzymes also showed strong anti-amnesic activities at doses of 1-5 mg/kg, i.p.
已合成了几种吡咯烷衍生物，并检测了它们对来自脑膜败血黄杆菌和牛脑的脯氨酸裂解酶的抑制活性。本研究中测试的几乎所有化合物在低IC50值（从纳摩尔到微摩尔）时均抑制这两种酶的活性，但观察到烷基酰基 - 肽基 - 吡咯烷衍生物存在特异性差异，其仅强烈抑制细菌酶。最有效的抑制剂在其P2位点有一个脯氨酸残基，在其P3位点有一个取代或未取代的苯氧基丁酰基部分。因此，苯氧基丁酰基 - 脯氨酰 - 吡咯烷是抑制剂最有效的部分结构。发现的最佳抑制剂为：对细菌酶的4 - （4 - 苄基苯氧基）丁酰基 - 脯氨酰 - 吡咯烷（IC50 1.4纳摩尔）和对牛脑酶的4 - 苯基丁酰基 - 硫代脯氨酰 - 吡咯烷（IC50 67纳摩尔）。在被动回避试验中，使用东莨菪碱实验诱导的失忆大鼠，对脯氨酸裂解酶具有强效抑制活性的吡咯烷衍生物在腹腔注射1 - 5毫克/千克的剂量下也表现出强烈的抗失忆活性。
