Novel scaffold evolution through combinatorial 3D-QSAR model studies of two types of JNK3 inhibitors
Novel scaffold evolution through combinatorial 3D-QSAR model studies of two types of JNK3 inhibitors
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DOI：
10.1016/j.bmcl.2017.03.063
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发表时间：
2017-05-15
影响因子：
2.7
通讯作者：
Hah, Jung-Mi
中科院分区：
文献类型：
--
作者：
Jung, Hoyong;Aman, Waciar;Hah, Jung-Mi
JNK 3是包括AD和PD在内的神经退行性疾病的新兴靶标，具有组织学选择性。具体而言，在AD中，JNK 3是APP磷酸化的主要蛋白激酶，APP磷酸化是A β加工的重要机制，也是阿尔茨海默病的生物标志物。因此，靶向JNK 3是神经退行性疾病药物发现的合理策略。为了找到一种新的JNK 3抑制剂的支架，我们用两种不同的JNK 3抑制剂系列进行了3D-QSAR建模研究。CoMFA模型的q（2）值为0.806，r（2）值为0.850。在CoMFA和CoMSIA模型的基础上，进行合理设计，得到了一种新型的骨架化合物N-（噻吩-2-基）-8H-吡唑并[1，5-a]吡啶并[1，2-c]嘧啶-10-甲酰胺。(C)2017爱思唯尔有限公司版权所有
JNK3 is an emerging target for neurodegenerative diseases including AD and PD, with histological selectivity. Specifically, in AD, JNK3 is the main protein kinase for APP phosphorylation, which is an important mechanism for A beta processing, and a biomarker of Alzheimer's disease. Therefore, targeting JNK3 is a reasonable strategy for drug discovery in neurodegenerative diseases. In order to find a novel scaffold for JNK3 inhibitors, we performed 3D-QSAR modeling studies with two different JNK3 inhibitor series. The CoMFA model was obtained with a q(2) value of 0.806 and an r(2) value of 0.850. Based on CoMFA and CoMSIA models, rational design was conducted and led to a novel scaffold, N-(thiophen-2-yl)-8H-pyrazolo [1,5-a]pyrido [1,2-c]pyrimidine-10-carboxamide. (C) 2017 Elsevier Ltd. All rights reserved.