Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
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.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.3c00498 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
S1P/S1PR4 Promotes the Differentiation of CD8 tissue-resident memory T Cells Aggravating Bile Duct Injury in Biliary Atresia.
J Hepatol
September 2025
Department of Neonatal Surgery, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China. Electronic address:
Background And Aims: Biliary atresia (BA) is a severe neonatal cholangiopathy characterized by progressive inflammation and fibrosis. We aimed to systematically investigate BA pathology using integrated multi-omics.
Methods: Multi-omics integration of BA and control livers revealed sphingolipid dysregulation.
Subcutaneous administration of the sphingosine kinase 2 inhibitor ABC294640 has no metabolic benefits in high fat diet-induced obesity in male mice.
Life Sci
September 2025
Department of Experimental Medical Science, Faculty of Medicine, Lund University, 221 84, Lund, Sweden; Wallenberg Center for Molecular Medicine, Faculty of Medicine, Lund University, 221 84, Lund, Sweden. Electronic address:
Aims: Experimental evidence suggests an important role for sphingosine-1-phosphate (S1P) and its generating enzymes sphingosine kinase 1/2 (SphK1/2) in obesity. We and others have shown that plasma S1P levels are elevated in obese mice and humans. Preclinical studies suggest that genetic SphK2 ablation in mice protects from age- and diet-induced obesity and metabolic dysfunction.
View Article and Find Full Text PDFA Randomized Trial on the Combined Effect of Ponesimod and Propranolol on Heart Rate, Cardiac Safety, and Pharmacokinetics in Healthy Adults.
Clin Transl Sci
September 2025
Johnson & Johnson, Allschwil, Switzerland.
The objective of this phase 1 study was to evaluate the pharmacokinetics (PK), pharmacodynamics, and cardiac effect following administration of ponesimod (a selective sphingosine-1-phosphate receptor modulator) and propranolol in healthy adults. In treatment period (TP) 1, participants received ponesimod (2 mg). In TP2, if resting heart rate (HR) was ≥ 55 bpm, the ponesimod up-titration regimen was initiated.
View Article and Find Full Text PDFDiscovery and SAR study of highly selective and potent 1,2,4-oxadiazole-based S1PR1 agonists.
Eur J Med Chem
August 2025
School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China. Electronic address:
Sphingosine-1-phosphate receptor 1 (S1PR1) is a validated therapeutic target for immune-mediated diseases such as multiple sclerosis and ulcerative colitis, owing to its critical role in regulating of lymphocyte migration. However, the clinical utility of current S1PR1 agonists is often limited by cardiovascular adverse effects, particularly dose-dependent bradycardia. Enhancing receptor subtype selectivity represents a promising strategy to mitigate these risks.
View Article and Find Full Text PDFBeyond High-density Lipoprotein-cholesterol: Unraveling the Complexity of High-density Lipoprotein Functionality.
J Atheroscler Thromb
September 2025
Center for Preventive Medicine, The Jikei University Hospital.
High-density lipoprotein (HDL) levels have long been inversely associated with cardiovascular disease (CVD) and are traditionally evaluated by serum HDL-cholesterol (HDL-C) levels. However, recent studies have raised doubts regarding the causal role of HDL quantity (HDL-C), drawing attention to HDL functionality. Reverse cholesterol transport (RCT) is a major anti-atherosclerotic mechanism involving ATP-binding cassette A1 (ABCA1), ATP-binding cassette G1 (ABCG1), scavenger receptor class B type I (SRB1), and regulatory factors, such as liver X receptor (LXR) and peroxisome proliferator-activated receptor gamma (PPARγ).
View Article and Find Full Text PDF