Kaminski J M, Bauer L, Mack S R, Anderson R A, Waller D P, Zaneveld L J
J Med Chem. 1986 Apr;29(4):514-9. doi: 10.1021/jm00154a015.
The aryl 4-guanidinobenzoate, 4'-nitrophenyl 4-guanidinobenzoate (NPGB), is a potent inhibitor of sperm acrosin, an enzyme with an essential function in the fertilization process. NPGB prevents fertilization in a number of animal species and is a good lead compound for the development of contraceptive agents. In order to assess the efficacy of other aryl 4-guanidinobenzoates as acrosin inhibitors, 24 of these compounds were synthesized. Their inhibitory activity toward human acrosin was determined and compared with their activity toward human pancreatic trypsin in order to assess whether inhibitor sensitivity differed between these similar enzymes. Nine of the inhibitors were synthesized from phenols approved by the FDA for therapeutic use. The acute toxicity of these inhibitors in mice was determined and compared to that of nonoxynol-9, the most commonly used active ingredient in today's vaginal contraceptive preparations. All of the compounds proved to be potent inhibitors of human acrosin although 3 orders of magnitude difference were observed between the most and least effective inhibitors. Little specificity was present in regard to their inhibition of acrosin and trypsin. All the aryl 4-guanidinobenzoates synthesized from FDA-approved phenols were less toxic than nonoxynol-9, and it is concluded that these 4-guanidinobenzoates are of interest for further development and testing as nonhormonal contraceptive agents.
芳基4-胍基苯甲酸酯，4'-硝基苯基4-胍基苯甲酸酯（NPGB），是精子顶体蛋白酶的一种强效抑制剂，顶体蛋白酶在受精过程中具有重要作用。NPGB能阻止多种动物物种的受精，是开发避孕药物的良好先导化合物。为了评估其他芳基4-胍基苯甲酸酯作为顶体蛋白酶抑制剂的功效，合成了其中24种化合物。测定了它们对人顶体蛋白酶的抑制活性，并与它们对人胰蛋白酶的活性进行比较，以评估这些相似酶之间抑制剂敏感性是否存在差异。其中9种抑制剂是由美国食品药品监督管理局（FDA）批准用于治疗的酚类合成的。测定了这些抑制剂对小鼠的急性毒性，并与壬苯醇醚-9（当今阴道避孕制剂中最常用的活性成分）的急性毒性进行比较。所有化合物均被证明是人类顶体蛋白酶的强效抑制剂，尽管最有效和最无效的抑制剂之间存在3个数量级的差异。它们对顶体蛋白酶和胰蛋白酶的抑制作用几乎没有特异性。所有由FDA批准的酚类合成的芳基4-胍基苯甲酸酯的毒性均低于壬苯醇醚-9，得出的结论是，这些4-胍基苯甲酸酯作为非激素避孕药物值得进一步开发和测试。
