Department of Molecular Therapeutics, and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way A2A, Jupiter, Florida 33458, USA.
J Med Chem. 2010 Jan 14;53(1):419-31. doi: 10.1021/jm901351f.
Given the significant body of data supporting an essential role for c-jun-N-terminal kinase (JNK) in neurodegenerative disorders, we set out to develop highly selective JNK inhibitors with good cell potency and good brain penetration properties. The structure-activity relationships (SAR) around a series of aminopyrimidines were evaluated utilizing biochemical and cell-based assays to measure JNK inhibition and brain penetration in mice. Microsomal stability in three species, P450 inhibition, inhibition of generation of reactive oxygen species (ROS), and pharmacokinetics in rats were also measured. Compounds 9g, 9i, 9j, and 9l had greater than 135-fold selectivity over p38, and cell-based IC(50) values < 100 nM. Moreover, compound 9l showed an IC(50) = 0.8 nM for inhibition of ROS and had good pharmacokinetic properties in rats along with a brain-to-plasma ratio of 0.75. These results suggest that biaryl substituted aminopyrimidines represented by compound 9l may serve as the first small molecule inhibitors to test efficacy of JNK inhibitors in neurodegenerative disorders.
鉴于 c-jun-N 末端激酶 (JNK) 在神经退行性疾病中具有重要作用的大量数据，我们着手开发具有良好细胞效力和良好脑穿透特性的高度选择性 JNK 抑制剂。利用生化和基于细胞的测定法评估了一系列氨基嘧啶的结构-活性关系 (SAR)，以测量 JNK 抑制和在小鼠中的脑穿透。还测量了三种物种中的微粒体稳定性、CYP450 抑制、活性氧 (ROS) 生成的抑制以及大鼠的药代动力学。化合物 9g、9i、9j 和 9l 对 p38 的选择性大于 135 倍，并且基于细胞的 IC50 值<100 nM。此外，化合物 9l 对 ROS 的抑制具有 IC50 = 0.8 nM，并且在大鼠中具有良好的药代动力学特性，脑-血浆比为 0.75。这些结果表明，以化合物 9l 为代表的二芳基取代的氨基嘧啶可能成为第一个小分子抑制剂，用于测试 JNK 抑制剂在神经退行性疾病中的疗效。
