Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase
Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase
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DOI：
10.1021/jm0310986
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发表时间：
2005-07-14
影响因子：
7.3
通讯作者：
Gotteland, JP
中科院分区：
文献类型：
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作者：
Gaillard, P;Jeanclaude-Etter, I;Gotteland, JP
几条证据支持c-Jun N-末端激酶（JNK）在广泛的疾病中起关键作用的假设，所述疾病包括细胞死亡（凋亡）相关的病症（神经变性疾病、脑、心脏和肾缺血、癫痫）和炎性病症（多发性硬化、类风湿性关节炎、炎性肠病）。筛选我们的JNK 3抑制剂的内部化合物集合，鉴定出（苯并噻唑-2-基）乙腈衍生物为有效和选择性JNK 1，-2，-3抑制剂。从初始命中1（AS 007149）开始，探索了这种新型和独特的激酶抑制剂模板的化学和初始结构-活性关系（SAR）。SAR的研究迅速揭示了苯并噻唑-2-基乙腈嘧啶核心对于保持对大鼠JNK 3的良好效力水平至关重要。因此，化合物6通过探索许多远端组合代替氯原子而进一步优化。这导致观察到，芳香族基团的存在，距离氨基嘧啶部分两个碳并且带有赋予氢键受体（HBA）性质的取代基，可以提高效力。对最有前途的化合物的生物学和生物制药学特征进行了进一步改进，从而发现了化合物59（AS 601245）。研究了这种新型JNK抑制剂的体外和体内抗炎潜力，发现其在类风湿性关节炎（RA）实验模型中经口给药的有效性。
Several lines of evidence support the hypothesis that c-Jun N-terminal kinase (JNKs) plays a critical role in a wide range of diseases including cell death (apoptosis)-related disorders (neurodegenerative diseases, brain, heart, and renal ischemia, epilepsy) and inflammatory disorders (multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases). Screening of our internal compound collection for inhibitors of JNK3 led to the identification of (benzothiazol-2-yl)acetonitrile derivatives as potent and selective JNK1, -2, -3 inhibitors. Starting from initial hit 1 (AS007149), the chemistry and initial structure-activity relationship (SAR) of this novel and unique kinase inhibitor template were explored. Investigation of the SAR rapidly revealed that the benzothiazol-2-ylacetonitrile pyrimidine core was crucial to retain a good level of potency on rat JNK3. Therefore, compound 6 was further optimized by exploring a number of distal combinations in place of the chlorine atom. This led to the observation that the presence of an aromatic group, two carbons away from the aminopyrimidine moiety and bearing substituents conferring hydrogen bond acceptor (HBA) properties, could improve the potency. Further improvements to the biological and biopharmaceutical profile of the most promising compounds were performed, resulting in the discovery of compound 59 (AS601245). The in vitro and in vivo anti-inflammatory potential of this new JNK inhibitor was investigated and found to demonstrate efficacy per oral route in an experimental model of rheumatoid arthritis (RA).