Delving into the Latest Updates on S1PR1 agonist(Shanghai Fosun) with Synapse

Overview

Basic Info

Drug Type

Chemical drugs

Synonyms-

Target

S1PR1

Action

agonists

Mechanism

S1PR1 agonists(Sphingosine 1-phosphate receptor Edg-1 agonists)

Therapeutic Areas

Immune System DiseasesDigestive System Disorders

Active Indication-

Inactive Indication

Inflammatory Bowel Diseases

Originator Organization

Shanghai Fosun Pharmaceutical (Group) Co., Ltd.

Active Organization-

Inactive Organization

Shanghai Fosun Pharmaceutical (Group) Co., Ltd.

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Sphingosine-1-phosphate receptor 1 (S1PR1), a member of the G protein-coupled receptor (GPCR) family, is a crucial therapeutic target for various diseases. Activation of S1PR1 has been recognized as an effective therapeutic strategy for multiple sclerosis (MS), inflammatory bowel disease (IBD), and psoriasis. Natural products (NPs) serve as a rich source of bioactive compounds for drug discovery. Here, we aimed to discover novel S1PR1 agonists from NPs via multi-level virtual screening (VS). Using a validated HipHop pharmacophore model, we screened a database containing 54,642 NPs, followed by molecular docking. Based on binding mode analysis, four candidate S1PR1 agonists (NPC323626, NPC264112, NPC469907, and NPC22192) were selected. Subsequent molecular dynamics (MD) simulations and binding free energy calculations confirmed the stability of the receptor-ligand complexes and their binding affinities. Among the four candidates, NPC469907 exhibited the strongest binding affinity for S1PR1, with a value of -58.08 ± 0.13 kJ/mol. Furthermore, hydrogen bonds formed between NPC469907 and Glu121 of S1PR1 were found to be essential for receptor activation. Quantum mechanical calculations further revealed that the phenyl-ring-attached hydrogen site in NPC469907 could be modified without compromising its ability to activate S1PR1. The analysis of Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) indicated that NPC469907 possessed favorable pharmacokinetic properties and low toxicity. In conclusion, our study identified NPC469907 as a promising natural S1PR1 agonist and established an effective VS strategy for the discovery of novel S1PR1 agonists.

01 Jul 2026·EUROPEAN JOURNAL OF PAIN

Effects of Selective Sphingosine‐1‐Phosphate Receptor 1 Agonist, TRV045 , on Evoked Pain Tests: An Exploratory, Four‐Way Cross‐Over Study in Healthy Volunteers

Article

Author: Hijma, Hemme J. ; Eijsvogel, P. ; Chen, Ruihua ; Bakker, Wouter A. ; Dahan, Albert ; Kim, Jessica ; Niesters, Marieke ; Groeneveld, Geert Jan ; Demitrack, Mark A. ; Klaassen, Erica S.

ABSTRACT:

Introduction:

Preclinical evidence suggests that dysregulation of the ceramide‐sphingosine‐1‐phosphate (S1P) axis may have analgesic properties. However, currently approved S1PR1 modulators such as fingolimod are hindered for this indication as they induce lymphopenia. The aim of the current study was to evaluate whether the novel, selective S1PR1 agonist TRV045 has analgesic effects in a validated evoked pain test battery in healthy volunteers.

Methods:

In this randomized, double‐blind, double‐dummy, placebo‐controlled, four‐way cross‐over study, 25 male or female healthy volunteers were randomized to receive either placebo or TRV045 50, 150 or 300 mg at separate occasions. The primary endpoint was heat pain detection threshold on UVB‐induced inflammatory pain. Secondary endpoints included analgesic reduction of capsaicin‐induced allodynia and pain detection and tolerance thresholds to evoked cold, electrical, pressure and heat pain. Furthermore, safety, tolerability and pharmacokinetics were monitored throughout the study. Data analyses included a repeated‐measures mixed‐effects model.

Results:

TRV045 was well tolerated, without serious adverse events. Compared to placebo, TRV045 did not reduce heat pain detection thresholds on UVB‐exposed skin, but significantly reduced the secondary area of capsaicin‐induced pain for the higher dose levels: 150 mg: −304.10 mm 2 (95% CI: −494.78 to −113.43, p = 0.002); 300 mg: −298.51 mm 2 (−486.83 to −110.20, p = 0.002). No effects on peripheral lymphocyte count were observed.

Conclusion:

TRV045 is a well‐tolerated S1PR1 modulator with analgesic properties in healthy volunteers as measured by the capsaicin‐induced pain model, which provides initial clinical evidence that selective S1PR1 modulation may be an appropriate novel target for the treatment of neuropathic pain.

Significance Statement:

Selective S1PR1 modulation produced analgesic effects in a validated human experimental pain model. This study provides clinical proof‐of‐concept for S1PR1 as a promising therapeutic target for neuropathic pain.

14 May 2026·JOURNAL OF MEDICINAL CHEMISTRY

Rational Design, Synthesis, and Biological Evaluation of Potent, Highly Selective 1,2,4-Oxadiazole-Based S1PR1 Agonists for UC Treatment

Article

Author: Huang, Simeng ; Wang, Rui ; Jin, Shengliang ; Yu, Jinling ; Xu, Zhongping ; Zhang, Luqi ; Xiao, Yunping ; Ye, Tianyu ; He, Huan ; Li, Honglin ; Zhao, Zhenjiang ; Wang, Ranran ; Tang, Chenyang ; Zhu, Lili

Sphingosine-1-phosphate receptor 1 is a clinically validated therapeutic target for ulcerative colitis. Substantial clinical evidence indicates that highly selective S1PR3-sparing S1PR1 agonists exhibit improved safety, making selectivity enhancement crucial in drug development. We report the rational design and synthesis of 3-aryl-5-bisaryl-1,2,4-oxadiazole derivatives as novel S1PR1 agonists. Among them, TYY-31 displayed single-digit picomolar activity against S1PR1 (EC₅₀ = 1.13 pM) with minimal activity against S1PR2/3/5 (EC₅₀ > 10 μM) and over 30,000-fold selectivity for S1PR1 compared to S1PR4. TYY-31 efficiently induced S1PR1 internalization (EC₅₀ = 0.73 nM) and blocked receptor recycling. Moreover, TYY-31 demonstrates outstanding pharmacokinetic properties. In vivo, TYY-31 effectively ameliorating dextran sulfate sodium-induced colitis in mice at a dose of 0.3 mg/kg, comparable to Ozanimod (1 mg/kg). Additionally, TYY-31 demonstrated excellent cardiac safety characteristics in zebrafish-based assays. These findings highlight TYY-31 as a highly selective and potent S1PR1 agonist with promising potential as a candidate drug for UC treatment.

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