Pharmaceutical Sciences Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Discovery Research Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Eur J Med Chem. 2020 Oct 1;203:112521. doi: 10.1016/j.ejmech.2020.112521. Epub 2020 Jul 5.
We previously reported that MGS0008 is a selective group II metabotropic glutamate receptor (mGlu2/3 receptor) agonist that is effective in animal models of schizophrenia. MGS0008 is a highly hydrophilic glutamate analog and is therefore expected to show low oral bioavailability in humans. To improve the oral bioavailability of MGS0008, ester prodrugs of MGS0008 were synthesized and their usefulness was evaluated. Among the prodrugs, the l-menthol-ester prodrug 4h demonstrated preferable lipophilicity, good chemical stability, and a high conversion rate to MGS0008 in human and monkey liver microsomes. A pharmacokinetic study in monkeys revealed that the oral bioavailability of MGS0008 after oral dosing of compound 4h was approximately 15-fold higher than that after oral dosing of MGS0008. Based on these findings, a diastereomer of compound 4h (compound 4j, or MGS0274), was selected as a candidate for clinical drug development, and its besylate is currently under development for the treatment of schizophrenia (Development code: TS-134).
我们之前报道过，MGS0008 是一种选择性的 II 型代谢型谷氨酸受体（mGlu2/3 受体）激动剂，在精神分裂症动物模型中有效。MGS0008 是一种高度亲水性的谷氨酸类似物，因此预计在人体中口服生物利用度较低。为了提高 MGS0008 的口服生物利用度，我们合成了 MGS0008 的酯前药，并对其进行了评估。在这些前药中，l-薄荷醇酯前药 4h 表现出较好的亲脂性、良好的化学稳定性，并且在人肝微粒体和猴肝微粒体中能够高效转化为 MGS0008。在猴子中的药代动力学研究表明，口服给予化合物 4h 后，MGS0008 的口服生物利用度约为口服给予 MGS0008 的 15 倍。基于这些发现，化合物 4h 的非对映异构体（化合物 4j，或 MGS0274）被选为临床药物开发的候选药物，其苯磺酸盐目前正在开发用于治疗精神分裂症（开发代码：TS-134）。
