Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
Bioorg Med Chem. 2019 Aug 1;27(15):3440-3450. doi: 10.1016/j.bmc.2019.06.021. Epub 2019 Jun 19.
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-á-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.
我们开发了一类新型的 PDE10A 抑制剂，即吡唑并[1,5-a]嘧啶衍生物 MT-3014（1）。由于担心核心二苯乙烯结构的 E/Z-异构化和谷胱甘肽加合物形成，之前引入的化合物被降为次要地位。我们通过利用与 PDE10A 的共晶结构的基于结构的药物设计发现了吡唑并[1,5-a]嘧啶作为一种新的先导骨架。通过优化先导化合物的体外活性、溶解度和对人 ether-á-go-go 相关基因心脏通道结合的选择性，对其进行了优化。我们观察到 MT-3014 在大鼠条件回避反应试验中表现出优异的疗效，并且在大鼠体内具有合适的药代动力学特性，尤其是高脑穿透性。
