Vyera Pharmaceuticals, LLC , 600 Third Avenue, 10th Floor , New York , New York 10016 , United States.
Evotec (UK) LTD. , Alderley Park , Cheshire SK104TG , U.K.
J Med Chem. 2019 Feb 14;62(3):1562-1576. doi: 10.1021/acs.jmedchem.8b01754. Epub 2019 Jan 24.
A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine (1), for Toxoplasma gondii DHFR ( TgDHFR) relative to human DHFR ( hDHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between TgDHFR and hDHFR. Compound 2 improves TgDHFR selectivity 6.6-fold and potency 16-fold relative to 1. Here, we report on the optimization and structure-activity relationships of this arylpiperazine series leading to the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3. Compound 3 has a TgDHFR IC of 1.57 ± 0.11 nM and a hDHFR to TgDHFR selectivity ratio of 196, making it 89-fold more potent and 16-fold more selective than 1. Compound 3 was highly effective in control of acute infection by highly virulent strains of T. gondii in the murine model, and it possesses the best combination of selectivity, potency, and prerequisite drug-like properties to advance into IND-enabling, preclinical development.
一种更安全的弓形虫病治疗方法是通过提高二氢叶酸还原酶（DHFR）抑制剂的选择性和效力来实现，例如二甲氧嘧啶（1），使其对刚地弓形虫 DHFR（TgDHFR）相对于人 DHFR（hDHFR）。我们之前报道了通过对 TgDHFR 和 hDHFR 结合口袋之间的关键差异进行计算机建模来设计间联苯类似物 2。与 1 相比，化合物 2 将 TgDHFR 的选择性提高了 6.6 倍，效力提高了 16 倍。在这里，我们报告了该芳基哌嗪系列的优化和构效关系的研究，从而发现了 5-(4-(3-(2-甲氧基嘧啶-5-基)苯基)哌嗪-1-基)嘧啶-2,4-二胺 3。化合物 3 对 TgDHFR 的 IC 为 1.57±0.11 nM，对 hDHFR 的选择性比值为 196，使其比 1 更有效 89 倍，更有效 16 倍。在鼠模型中，化合物 3 对高毒力刚地弓形虫株的急性感染具有高度疗效，并且具有选择性、效力和必需的药物样特性的最佳组合，可推进 IND 许可前的临床前开发。
