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).

我们先前曾报道，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，在精神分裂症的动物模型中有效。MGS0008是一种高度亲水的谷氨酸类似物，因此有望在人类中显示出较低的口服生物利用度。为了提高MGS0008的口服生物利用度，合成了MGS0008的酯前药并评估了其实用性。在前药中，1-薄荷醇酯前药4h在人和猴肝微粒体中表现出较好的亲脂性，良好的化学稳定性和向MGS0008的高转化率。猴子的药代动力学研究表明，口服化合物4h后MGS0008的口服生物利用度比口服MGS0008后高约15倍。基于这些发现，选择了化合物4h（化合物4j，或MGS0274）的非对映异构体作为临床药物开发的候选药物，目前正在开发其苯磺酸盐用于治疗精神分裂症（开发代码：TS-134）。