Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76-78, 24118 Kiel, Germany.
ChemMedChem. 2011 Dec 9;6(12):2233-42. doi: 10.1002/cmdc.201100422. Epub 2011 Oct 7.
Pentamidine is an effective antimicrobial agent that is approved for the treatment of African trypanosomiasis but suffers from poor oral bioavailability and central nervous system (CNS) penetration. This work deals with the development and systematic characterisation of new prodrugs of pentamidine. For this reason, numerous prodrugs that use different prodrug principles were synthesised and examined in vitro and in vivo. Another objective of the study was the determination of permeability of the different pentamidine prodrugs. While some of the prodrug principles applied in this study are known, such as the conversion of the amidine functions into amidoximes or the O-alkylation of amidoximes with a carboxymethyl residue, others were developed more recently and are described here for the first time. These newly developed methods aim to increase the affinity of the prodrug for the transporters and mediate an active uptake via carrier systems by conjugation of amidoximes with compounds that improve the overall solubility of the prodrug. The different principles chosen resulted in several pentamidine prodrugs with various advantages. The objective of this investigation was the systematic characterisation and evaluation of eight pentamidine prodrugs in order to identify the most appropriate strategy to improve the properties of the parent drug. For this reason, all prodrugs were examined with respect to their solubility, stability, enzymatic activation, distribution, CNS delivery, and oral bioavailability. The results of this work have allowed reliable conclusions to be drawn regarding the best prodrug principle for the antiprotozoal drug pentamidine.
戊二脒是一种有效的抗菌药物，已被批准用于治疗非洲锥虫病，但口服生物利用度和中枢神经系统（CNS）渗透性差。这项工作涉及戊二脒的新型前药的开发和系统表征。为此，合成并研究了许多使用不同前药原理的前药，以评估其体外和体内效果。研究的另一个目的是确定不同戊二脒前药的通透性。虽然本研究中应用的一些前药原理是已知的，例如将脒基转化为脒肟或用羧甲基残基对脒肟进行 O-烷基化，但其他原理是最近开发的，并在此首次描述。这些新开发的方法旨在通过将脒肟与可提高前药整体溶解性的化合物偶联，增加前药与转运体的亲和力，并通过载体系统介导主动摄取，从而提高前药的亲和力。所选择的不同原理导致了几种具有不同优势的戊二脒前药。本研究的目的是系统地表征和评估八种戊二脒前药，以确定改善母体药物性质的最合适策略。因此，所有前药都进行了溶解度、稳定性、酶促激活、分布、CNS 传递和口服生物利用度的检测。这项工作的结果使我们能够就抗原生动物药物戊二脒的最佳前药原理得出可靠的结论。
