Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrechts-University of Kiel, Gutenbergstr. 76-78, D-24118 Kiel, Germany.
Bioorg Med Chem. 2011 Mar 15;19(6):1907-14. doi: 10.1016/j.bmc.2011.01.066. Epub 2011 Feb 3.
In general, drugs containing amidines suffer from poor oral bioavailability and are often converted into amidoxime prodrugs to overcome low uptake from the gastrointestinal tract. The esterification of amidoximes with amino acids represents a newly developed double prodrug principle creating derivatives of amidines with both improved oral availability and water solubility. N-valoxybenzamidine (1) is a model compound for this principle, which has been transferred to the antiprotozoic drug pentamidine (8). Prodrug activation depends on esterases and mARC and is thus independent from activation by P450 enzymes. Therefore, drug-drug interactions or side effects will be minimized. The synthesis of these two compounds was established, and their biotransformation was studied in vitro and in vivo. Bioactivation of N-valoxybenzamidine (1) and N,N'-bis(valoxy)pentamidine (7) via hydrolysis and reduction has been demonstrated in vitro with porcine and human subcellular enzyme preparations and the mitochondrial Amidoxime Reducing Component (mARC). Moreover, activation of N-valoxybenzamidine (1) by porcine hepatocytes was studied. In vivo, the bioavailability in rats after oral application of N-valoxybenzamidine (1) was about 88%. Similarly, N,N'-bis(valoxy)pentamidine (7) showed oral bioavailability. Analysis of tissue samples revealed high concentrations of pentamidine (8) in liver and kidney.
一般来说，含脒基的药物口服生物利用度较差，常被转化为羟肟酸前药以克服从胃肠道吸收不良的问题。羟肟酸与氨基酸的酯化代表了一种新开发的双重前药原理，可使脒类衍生物具有更好的口服生物利用度和水溶性。N-羟肟酸苄脒（1）是该原理的模型化合物，已被转移到抗原生动物药物戊脒（8）中。前药的激活依赖于酯酶和 mARC，因此与 P450 酶的激活无关。因此，药物相互作用或副作用将最小化。建立了这两种化合物的合成方法，并研究了它们在体外和体内的生物转化。已经在猪和人亚细胞酶制剂和线粒体羟肟酸还原成分（mARC）中体外证明了 N-羟肟酸苄脒（1）和 N，N'-双（羟肟）戊脒（7）通过水解和还原的生物活化。此外，还研究了猪肝细胞中 N-羟肟酸苄脒（1）的激活。在体内，口服给予 N-羟肟酸苄脒（1）后大鼠的生物利用度约为 88%。同样，N，N'-双（羟肟）戊脒（7）也具有口服生物利用度。组织样品分析显示肝和肾中戊脒（8）浓度较高。
