Gonzàlez Cabrera Diego, Douelle Frederic, Le Manach Claire, Han Ze, Paquet Tanya, Taylor Dale, Njoroge Mathew, Lawrence Nina, Wiesner Lubbe, Waterson David, Witty Michael J, Wittlin Sergio, Street Leslie J, Chibale Kelly
Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town 7925, South Africa.
J Med Chem. 2015 Sep 24;58(18):7572-9. doi: 10.1021/acs.jmedchem.5b01156. Epub 2015 Sep 8.
Based on the initial optimization of orally active antimalarial 2,4-diamino-thienopyrimidines and with the help of metabolite identification studies, a second generation of derivatives involving changes at the 2- and 4-positions of the thienopyrimidine core were synthesized. Improvements in the physiochemical properties resulted in the identification of 15a, 17a, 32, and 40 as lead molecules with improved in vivo exposure. Furthermore, analogue 40 exhibited excellent in vivo antimalarial activity when dosed orally at 50 mg/kg once daily for 4 days in the Plasmodium berghei mouse model, which is superior to the activity seen with previously reported compounds, and with a slightly improved hERG profile.
基于口服活性抗疟药2,4-二氨基噻吩并嘧啶的初步优化，并借助代谢物鉴定研究，合成了第二代衍生物，这些衍生物在噻吩并嘧啶核心的2位和4位发生了变化。物理化学性质的改善使得15a、17a、32和40被鉴定为具有改善的体内暴露的先导分子。此外，在伯氏疟原虫小鼠模型中，类似物40以50mg/kg的剂量每日口服一次，连续给药4天，表现出优异的体内抗疟活性，优于先前报道的化合物，并且人醚-去极化激活的钾离子通道（hERG）特性略有改善。
