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Exploration of Tetrahydroisoquinoline- and Benzo[c]azepine-Based Sphingosine 1‑Phosphate Receptor 1 Agonists for the Treatment of Multiple Sclerosis
dataset
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 LimBecause 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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vitro cardiovascular safetyphosphate receptor 1improved safety profilesgeneration sphingosine 1favorable adme propertiescardiovascular side effects>] azepine core60 32 based s1p1 agonistsgeneration ms drugs>] azepinec s1p1 agonistsnew drugsagonist drugswide usevivo efficacysystematic examinationstill presentmultiple sclerosismolecular interactionshydrophilic groupshuman ipscem structureseae studiesderived cardiomyocytesclearly demonstratedbinding modesbenzo [<
