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Exploration of Tetrahydroisoquinoline- and Benzo[c]azepine-Based Sphingosine 1‑Phosphate Receptor 1 Agonists for the Treatment of Multiple Sclerosis

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posted on 2023-07-25, 12:11 authored by Eunji Cha, Jushin Kim, Lizaveta Gotina, Jaehwan Kim, Hyeon Jeong Kim, Seon Hee Seo, Jeong-Eun Park, Jeongmin Joo, Minsik Kang, Jaeick Lee, Hayoung Hwang, Hak Joong Kim, Ae Nim Pae, Ki Duk Park, Jong-Hyun Park, Sang Min Lim
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[c]azepine core-based S1P1 agonists such as 32 and 60 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.

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