GluN1 inhibitors(glutamate ionotropic receptor NMDA type subunit 1 inhibitors), GluN2B antagonists(Glutamate [NMDA] receptor subunit epsilon 2 antagonists)

Therapeutic Areas

Nervous System DiseasesCardiovascular Diseases

Active Indication

Ischemic stroke

Inactive Indication-

Originator Organization

Anhui University of Chinese Medicine

Active Organization

Anhui University of Chinese Medicine

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC21H19BrN4O2S

InChIKeyYVICAZJLKUSZMU-FPYGCLRLSA-N

CAS Registry-

100 Clinical Results associated with S-58

100 Translational Medicine associated with S-58

100 Patents (Medical) associated with S-58

Literatures (Medical) associated with S-58

14 Mar 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Design, Synthesis, and Biological Evaluation of Pierardine Derivatives as Novel Brain-Penetrant and In Vivo Potent NMDAR-GluN2B Antagonists for Ischemic Stroke Treatment

Q1 · MEDICINE

Article

Author: Yue, Shaoyun ; Zhu, Qihua ; Ye, Wenfeng ; Xu, Qinlong ; Fang, Tao ; Zhao, Yan ; Mo, Jiajia ; Shao, Li ; Dai, Mingqi ; He, Minghan ; Chu, Zhaoxing ; Lin, Gaofeng ; Li, Jiaming ; Ma, Xiaodong

A series of structurally novel GluN2B NMDAR antagonists were designed, synthesized, and biologically evaluated as anti-stroke therapeutics by optimizing the chemical structure of Pierardine, the active ingredient of traditional Chinese medicine Dendrobium aphyllum (Roxb.) C. E. Fischer identified via in silico screening. The systematic structure-activity relationship study led to the discovery of 58 with promising NMDAR-GluN2B binding affinity and antagonistic activity. Of the two enantiomers, S-58 exhibited significant inhibition (IC₅₀ = 74.01 ± 12.03 nM) against a GluN1/GluN2B receptor-mediated current in a patch clamp assay. In addition, it displayed favorable specificity over other subtypes and off-target receptors. In vivo, S-58 exerted therapeutic efficacy comparable to that of the approved GluN2B NMDAR antagonist ifenprodil and excellent safety profiles. In addition to the attractive in vitro and in vivo potency, S-58 exhibited excellent brain exposure. In light of these merits, S-58 has been advanced to further preclinical investigation as a potential anti-stroke candidate.

14 Mar 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of a Highly Potent Oxysterol Receptor GPR183 Antagonist Bearing the Benzo[d]thiazole Structural Motif for the Treatment of Inflammatory Bowel Disease (IBD)

Q1 · MEDICINE

Article

Author: Song, Zilan ; Zhu, Lingfeng ; Zhang, Ao ; Fang, Meimiao ; Rui, Weiwei ; Zeng, Ruoqing ; Feng, Bo ; Hong, Liang ; Liu, Mingyao ; Ding, Chunyong ; Shen, Ancheng ; Chai, Xiaolei ; Lu, Weiqiang ; Zhao, Yumiao

Accumulating evidence has demonstrated a critical pathological role of oxysterol receptor GPR183 in various inflammatory and autoimmune diseases, including inflammatory bowel disease (IBD). However, the currently reported GPR183 antagonists are very limited and not qualified for in vivo studies due to their inferior druglike properties. Herein, we conducted a structural elaboration focusing on improving its PK and safety profile based on a reference antagonist NIBR189. Of note, compound 33, bearing an aminobenzothiazole motif, exhibited reduced hERG inhibition, improved PK properties, and robust antagonistic activity (IC₅₀ = 0.82 nM) with high selectivity against GPR183. Moreover, compound 33 displayed strong in vitro antimigration and anti-inflammatory activity in monocytes. Oral administration of compound 33 effectively improved the pathological symptoms of DSS-induced experimental colitis. All of these findings demonstrate that compound 33 is a novel and promising GPR183 antagonist suitable for further investigation to treat IBD.

01 Sep 2023·iScience

The effect of GelDex-S58 hydrogel on anti-conjunctival scarring after glaucoma filtration surgery

Article

Author: Luo, Wangdu ; Li, Xiangji ; Jiang, Bingcai ; Lin, Qianyi ; Xie, Lin ; Tang, Min ; Lin, Yi

Excessive scarring is the main cause of surgical failure in glaucoma filtration surgery. S58 has been shown to have an excellent antifibrotic effect but its duration of action is not sufficient to achieve the desired antiscarring effect. In this study, a light-cured bioadhesive hydrogel composed of GelMA and oxidized dextran (ODex), namely, GelDex, was used to load S58 (GelDex-S58). The microscopic morphology of GelDex-S58 appeared to be a porous structure with good slow-release properties and suitable degradation time. Cell Counting Kit-8, cell scratch and transwell assays showed that GelDex-S58 significantly reduced TGF-β-induced fibroblast proliferation, increased migration and invasion ability. In in vivo studies, GelDex-S58 treatment prolonged follicular retention, reduced mean intraocular pressure, and significantly reduced collagen deposition and α-SMA expression levels in the conjunctival tissue compared to treatment with S58 alone. In conclusion, GelDex-S58 could reduce scar formation after glaucoma filtration surgery.

100 Deals associated with S-58

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Ischemic stroke	Preclinical	China	Anhui University of Chinese Medicine	27 Feb 2024

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