Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
J Med Chem. 2023 Aug 10;66(15):10381-10412. doi: 10.1021/acs.jmedchem.3c00498. Epub 2023 Jul 25.
Because of the wide use of Fingolimod for the treatment of multiple sclerosis (MS) and its cardiovascular side effects such as bradycardia, second-generation sphingosine 1-phosphate receptor 1 (S1P1) agonist drugs for MS have been developed and approved by FDA. The issue of bradycardia is still present with the new drugs, however, which necessitates further exploration of S1P1 agonists with improved safety profiles for next-generation MS drugs. Herein, we report a tetrahydroisoquinoline or a benzo[]azepine core-based S1P1 agonists such as and after systematic examination of hydrophilic groups and cores. We investigated the binding modes of our representative compounds and their molecular interactions with S1P1 employing recent S1P1 cryo-EM structures. Also, favorable ADME properties of our compounds were shown. Furthermore, in vivo efficacy of our compounds was clearly demonstrated with PLC and EAE studies. Also, the preliminary in vitro cardiovascular safety of our compound was verified with human iPSC-derived cardiomyocytes.
由于芬戈莫德（Fingolimod）被广泛用于多发性硬化症（MS）的治疗，且其具有心动过缓等心血管副作用，因此美国食品药品监督管理局（FDA）已批准了第二代鞘氨醇 1-磷酸受体 1（S1P1）激动剂类药物用于 MS 的治疗。然而，新药仍存在心动过缓的问题，因此需要进一步探索具有更好安全性特征的 S1P1 激动剂，以开发新一代 MS 药物。在此，我们报告了基于四氢异喹啉或苯并[ ]氮杂卓核的 S1P1 激动剂，如 和 ，在对亲水性基团和核进行系统研究后。我们利用最近的 S1P1 冷冻电镜结构研究了代表性化合物的结合模式及其与 S1P1 的分子相互作用。此外，我们还展示了化合物具有良好的 ADME 性质。此外，通过 PLC 和 EAE 研究，我们还明确证明了化合物的体内疗效。此外，还用人诱导多能干细胞衍生的心肌细胞验证了我们化合物的初步体外心血管安全性。
