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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 32and 60after 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.

NRF2 is considered as a master regulator of cellular defense system under stressed conditions such as oxidative stress. In physiological conditions, NRF2 forms a complex with Keap1‐Cul3 in the cytoplasm and undergoes ubiquitination and subsequent degradation. Under stressed conditions, the interaction between NRF2 and Keap1 is perturbed leading to NRF2 stabilization and migration to the nucleus where NRF2 activates genes accounting for antioxidative activities. Thus, small molecules that can disturb the interaction between NRF2 and Keap1 has been considered as promising for a variety of diseases. Herein, we report development of new, potent inhibitors of the interaction between NRF2 and Keap1 by deconvoluting previous inhibitors followed by structural hybridization. The most potent inhibitor identified by our FP assay showed IC50of 0.6 μM. We believe that our compounds will help to expand structural diversity of NRF2–Keap1 interaction inhibitors contributing to further development of promising candidates for various diseases. New, potent inhibitors of the interaction between NRF2 and Keap1 was designed and synthesized. Structural hybridization of fragments used in previous NRF2 and Keap1 interaction inhibitors was exploited and the most potent compound 17binhibited the interaction between NRF2 and Keap1 with an IC50value of 0.6 μM.