"Relative symmetry with electronegativity of different key-groups" strategy for MRGPRX2 antagonist design and its effect on antigen-induced pulmonary inflammation.
10.1016/j.apsb.2024.11.023
- Author:
Jiayu LU
1
;
Zhaomin XIA
1
;
Yongjing ZHANG
1
;
He WANG
2
;
Wen YANG
1
;
Siqi WANG
1
;
Nan WANG
1
;
Yun LIU
3
;
Huaizhen HE
1
;
Cheng WANG
1
;
Langchong HE
1
Author Information
1. School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
2. Key Laboratory of Synthetic and Natural Functional Molecule Chemistry (Ministry of Education), College of Chemistry and Materials Science, Northwest University, Xi'an 710069, China.
3. Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
- Publication Type:Journal Article
- Keywords:
Antagonist;
Antiallergic activity;
Antigen-induced pulmonary inflammation;
Diaryl urea;
Electrostatic complementarity;
MRGPRX2;
Relative symmetry with electronegativity;
Structure–activity relationships
- From:
Acta Pharmaceutica Sinica B
2025;15(1):494-507
- CountryChina
- Language:English
-
Abstract:
MRGPRX2 antagonists possess the potential for the treatment of allergic rhinitis, atopic dermatitis, and chronic urticaria. Previously, we identified a class of diaryl urea (DPU) MRGPRX2 antagonists with sub-micromolar IC50 values in vitro. However, the structure-activity relationship remains unclear. Herein, we adopted a "relative symmetry with electronegativity of different key-groups" strategy for further modification of DPUs to achieve a promising MRGPRX2 antagonist with higher activity and safety. Electrostatic potential energy analysis and biological evaluation revealed that B-1023 and B-5023, that possess relatively symmetric electron-withdrawing substituents, remarkable inhibited mast cell degranulation at a sub-micromolar IC50 in vitro and alleviated anaphylactic symptoms. Furthermore, B-1023, mitigated antigen-induced pulmonary inflammation (AIPI) in mice and competitively bonded to MRGPRX2. In summary, the "relative symmetry with electronegativity of different key-groups" strategy provided a drug design pattern for MRGPRX2 antagonists and identified promising antiallergic precursors for AIPI treatment.
