Li Zhongtang, Zhu Guiwang, Liu Xiaoang, Gao Tongfei, Fang Fan, Dou Xiaodong, Li Yiyan, Zheng Ruqiu, Jin Hongwei, Zhang Liangren, Liu Zhenming, Zhang Lihe
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
Eur J Med Chem. 2023 Mar 15;250:115167. doi: 10.1016/j.ejmech.2023.115167. Epub 2023 Feb 3.
An indolin-2-(4-thiazolidinone) scaffold was previously shown to be a novel chemotype for JNK3 inhibition. However, more in vivo applications were limited due to the unconfirmed configuration and poor physicochemical properties. Here, the indolin-2-(4-thiazolidinone) scaffold validated the absolute configuration; substituents on the scaffold were optimized. Extensive structure activity relationship (SAR) studies were performed using kinase activity assays, thus leading to potent and highly selective JNK3 inhibitors with neuroprotective activity and good oral bioavailability. One lead compound, A53, was a potent and selective JNK3 inhibitor (IC = 78 nM) that had significant inhibition (>80% at 1 μM) to only JNK3 in a 398-kinase panel. A53 had low inhibition against JNK3 and high stability (t = 0.98 h, t = 2.74 h) during oral administration. A modeling study of A53 in human JNK3 showed that the indolin-2-(4-thiazolidinone)-based JNK3 inhibitor with a 5-position-substituted hydrophilic group offered improved kinase inhibition.
先前已证明吲哚啉 - 2 -（4 - 噻唑烷酮）支架是一种用于抑制JNK3的新型化学类型。然而，由于构型未得到确认且物理化学性质不佳，其更多的体内应用受到限制。在此，吲哚啉 - 2 -（4 - 噻唑烷酮）支架的绝对构型得到了验证；对支架上的取代基进行了优化。使用激酶活性测定进行了广泛的构效关系（SAR）研究，从而得到了具有神经保护活性和良好口服生物利用度的强效且高度选择性的JNK3抑制剂。一个先导化合物A53是一种强效且选择性的JNK3抑制剂（IC = 78 nM），在398种激酶的检测中，它仅对JNK3有显著抑制作用（在1 μM时>80%）。A53在口服给药期间对JNK3的抑制作用较低且稳定性较高（t = 0.98 h，t = 2.74 h）。对人JNK3中A53的建模研究表明，具有5 - 位取代亲水基团的基于吲哚啉 - 2 -（4 - 噻唑烷酮）的JNK3抑制剂具有更好的激酶抑制作用。
