Veerman Johan, van den Bergh Toine, Orrling Kristina M, Jansen Chimed, Cos Paul, Maes Louis, Chatelain Eric, Ioset Jean-Robert, Edink Ewald E, Tenor Hermann, Seebeck Thomas, de Esch Iwan, Leurs Rob, Sterk Geert Jan
Mercachem, PO Box 6747, 6503 GE Nijmegen, The Netherlands.
Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute of Molecules, Medicines & Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Bioorg Med Chem. 2016 Apr 1;24(7):1573-81. doi: 10.1016/j.bmc.2016.02.032. Epub 2016 Feb 26.
Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. Knock down of both enzymes leads to cell cycle arrest and is lethal to the parasite. Recently, we reported the phenylpyridazinone, NPD-001, with low nanomolar IC50 values on both TbrPDEB1 (IC50: 4nM) and TbrPDEB2 (IC50: 3nM) (J. Infect. Dis.2012, 206, 229). In this study, we now report on the first structure activity relationships of a series of phenylpyridazinone analogs as TbrPDEB1 inhibitors. A selection of compounds was also shown to be anti-parasitic. Importantly, a good correlation between TbrPDEB1 IC50 and EC50 against the whole parasite was observed. Preliminary analysis of the SAR of selected compounds on TbrPDEB1 and human PDEs shows large differences which shows the potential for obtaining parasite selective PDE inhibitors. The results of these studies support the pharmacological validation of the Trypanosome PDEB family as novel therapeutic approach for HAT and provide as well valuable information for the design of potent TbrPDEB1 inhibitors that could be used for the treatment of this disease.
锥虫磷酸二酯酶B1和B2（TbrPDEB1和TbrPDEB2）在布氏锥虫的生命周期中发挥着重要作用，布氏锥虫是人类非洲锥虫病（HAT，又称非洲昏睡病）的致病寄生虫。两种酶的敲低会导致细胞周期停滞，并对寄生虫具有致死性。最近，我们报道了苯基哒嗪酮NPD - 001，它对TbrPDEB1（IC50：4nM）和TbrPDEB2（IC50：3nM）的IC50值均处于低纳摩尔水平（《传染病杂志》2012年，206卷，229页）。在本研究中，我们现在报告一系列苯基哒嗪酮类似物作为TbrPDEB1抑制剂的首次构效关系。还显示了一系列化合物具有抗寄生虫作用。重要的是，观察到TbrPDEB1的IC50与针对整个寄生虫的EC50之间具有良好的相关性。对所选化合物在TbrPDEB1和人磷酸二酯酶上的构效关系进行的初步分析显示出很大差异，这表明有可能获得寄生虫选择性磷酸二酯酶抑制剂。这些研究结果支持将锥虫磷酸二酯酶B家族作为治疗人类非洲锥虫病的新治疗方法进行药理学验证，并为设计可用于治疗该疾病的强效TbrPDEB1抑制剂提供了有价值的信息。
