Discovery of a pyrazolo[1,5-a] pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety
Discovery of a pyrazolo[1,5-a] pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety
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DOI：
10.1016/j.bmc.2019.06.021
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发表时间：
2019-08-01
影响因子：
3.5
通讯作者：
Kawanishi, Eiji
中科院分区：
文献类型：
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作者：
Koizumi, Yuuki;Tanaka, Yoshihito;Kawanishi, Eiji
我们开发了一类新的PDE 10A抑制剂，吡唑并[1，5-a]嘧啶衍生物MT-3014（1）。由于对E/Z-异构化和在核心芪结构处形成谷胱甘肽加合物的担忧，引入的先前化合物被降低优先级。我们发现吡唑并[1，5-a]嘧啶作为一种新的铅支架，通过基于结构的药物设计，利用与PDE 10A的共晶结构。对先导化合物的体外活性、溶解度和对人ether-a-go-go相关基因心脏通道结合的选择性进行了优化。我们观察到MT-3014在大鼠条件性回避反应试验中显示出优异的功效，并且在大鼠中显示出合适的药代动力学性质，尤其是高脑渗透性。
We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a] pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-a-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.