EuMentis Therapeutics Inc., 275 Grove Street, 2-400, Newton, MA 02466, USA.
MindImmune Therapeutics, Inc., Kingston, RI 02881, USA.
Cells. 2024 Jul 22;13(14):1230. doi: 10.3390/cells13141230.
Tourette syndrome is a neurodevelopmental movement disorder involving basal ganglia dysfunction. PDE10A inhibitors modulate signaling in the striatal basal ganglia nuclei and are thus of interest as potential therapeutics in treating Tourette syndrome and other movement disorders.
The preclinical pharmacology and toxicology, human safety and tolerability, and human PET striatal enzyme occupancy data for the PDE10A inhibitor EM-221 are presented.
EM-221 inhibited PDE10A with an in vitro IC50 of 9 pM and was >100,000 selective vs. other PDEs and other CNS receptors and enzymes. In rats, at doses of 0.05-0.50 mg/kg, EM-221 reduced hyperlocomotion and the disruption of prepulse inhibition induced by MK-801, attenuated conditioned avoidance, and facilitated novel object recognition, consistent with PDE10A's inhibition. EM-221 displayed no genotoxicity and was well tolerated up to 300 mg/kg in rats and 100 mg/kg in dogs. In single- and multiple-day ascending dose studies in healthy human volunteers, EM-221 was well tolerated up to 10 mg, with a maximum tolerated dose of 15 mg. PET imaging indicated that a PDE10A enzyme occupancy of up to 92.8% was achieved with a ~24 h half-life.
The preclinical and clinical data presented here support the study of EM-221 in phase 2 trials of Tourette syndrome and other movement disorders.
妥瑞氏症是一种涉及基底神经节功能障碍的神经发育运动障碍。PDE10A 抑制剂调节纹状体基底神经节核中的信号转导，因此作为治疗妥瑞氏症和其他运动障碍的潜在治疗药物具有很大的吸引力。
本文介绍了 PDE10A 抑制剂 EM-221 的临床前药理学和毒理学、人体安全性和耐受性以及人体 PET 纹状体酶占有率数据。
EM-221 对 PDE10A 的体外 IC50 为 9 pM，对其他 PDE 酶和其他中枢神经系统受体和酶的选择性 >100,000。在大鼠中，在 0.05-0.50 mg/kg 剂量下，EM-221 可减少 MK-801 诱导的过度运动和前脉冲抑制的破坏，减弱条件性回避，并促进新物体识别，与 PDE10A 的抑制作用一致。EM-221 无遗传毒性，在大鼠中高达 300 mg/kg 和狗中高达 100 mg/kg 的剂量下耐受性良好。在健康志愿者的单次和多日递增剂量研究中，EM-221 在高达 10 mg 时耐受性良好，最大耐受剂量为 15 mg。PET 成像表明，在 24 小时半衰期内可达到高达 92.8%的 PDE10A 酶占有率。
本文提供的临床前和临床数据支持 EM-221 用于妥瑞氏症和其他运动障碍的 2 期临床试验研究。
