2. Academic Validation
  3. Discovery and SAR study of highly selective and potent 1,2,4-oxadiazole-based S1PR1 agonists

Discovery and SAR study of highly selective and potent 1,2,4-oxadiazole-based S1PR1 agonists

  • Eur J Med Chem. 2025 Dec 15:300:118097. doi: 10.1016/j.ejmech.2025.118097.
Tianyu Ye 1,  Jinling Yu 1,  Yuxian Fang 1,  Zhongping Xu 1,  Shanshan Guo 1,  Zhenjiang Zhao 1,  Honglin Li 2,  Huan He 3,  Lili Zhu 4
Affiliations

Affiliations

  • 1 School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
  • 2 School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China; Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai, 200062, China. Electronic address: hlli@ecust.edu.cn.
  • 3 Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai, 200062, China. Electronic address: hhe@pharm.ecnu.edu.cn.
  • 4 School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China. Electronic address: zhulfl@ecust.edu.cn.
PMID: 40911968 DOI: 10.1016/j.ejmech.2025.118097
Abstract

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. Herein, we describe the discovery and optimization of a novel series of 1,2,4-oxadiazole-based S1PR1 agonists. Among these, Y18 exhibited potent agonistic activity toward S1PR1 (EC50 = 0.98 nM) with >10,000-fold selectivity over S1PR2, S1PR3, and S1PR5, as well as 109-fold selectivity over S1PR4. Functional studies demonstrated that Y18 efficiently induced S1PR1 internalization, blocked receptor recycling, and activated downstream ERK1/2 phosphorylation. The excellent selectivity across the S1PR family, along with its functional profile, supports Y18 as a promising candidate for S1PR1-targeted therapeutics.

Keywords

1,2,4-oxadiazole; S1PR1 agonist; S1PR1 internalization; Selectivity.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z