“Relative symmetry with electronegativity of different key-groups” strategy for MRGPRX2 antagonist design and its effect on antigen-induced pulmonary inflammation
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 unclea...
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Elsevier
2025-01-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383524004568 |
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| author | Jiayu Lu Zhaomin Xia Yongjing Zhang He Wang Wen Yang Siqi Wang Nan Wang Yun Liu Huaizhen He Cheng Wang Langchong He |
| author_facet | Jiayu Lu Zhaomin Xia Yongjing Zhang He Wang Wen Yang Siqi Wang Nan Wang Yun Liu Huaizhen He Cheng Wang Langchong He |
| author_sort | Jiayu Lu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-15b655a5b77e470384c877bc2af36cb6 |
| institution | DOAJ |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-15b655a5b77e470384c877bc2af36cb62025-08-20T03:11:37ZengElsevierActa Pharmaceutica Sinica B2211-38352025-01-0115149450710.1016/j.apsb.2024.11.023“Relative symmetry with electronegativity of different key-groups” strategy for MRGPRX2 antagonist design and its effect on antigen-induced pulmonary inflammationJiayu Lu0Zhaomin Xia1Yongjing Zhang2He Wang3Wen Yang4Siqi Wang5Nan Wang6Yun Liu7Huaizhen He8Cheng Wang9Langchong He10School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, ChinaSchool of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, ChinaSchool of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, ChinaKey Laboratory of Synthetic and Natural Functional Molecule Chemistry (Ministry of Education), College of Chemistry and Materials Science, Northwest University, Xi'an 710069, ChinaSchool of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, ChinaSchool of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, ChinaSchool of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, ChinaDepartment of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, ChinaSchool of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, ChinaSchool of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Corresponding authors.School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S2211383524004568MRGPRX2AntagonistDiaryl ureaRelative symmetry with electronegativityAntiallergic activityAntigen-induced pulmonary inflammation |
| spellingShingle | Jiayu Lu Zhaomin Xia Yongjing Zhang He Wang Wen Yang Siqi Wang Nan Wang Yun Liu Huaizhen He Cheng Wang Langchong He “Relative symmetry with electronegativity of different key-groups” strategy for MRGPRX2 antagonist design and its effect on antigen-induced pulmonary inflammation Acta Pharmaceutica Sinica B MRGPRX2 Antagonist Diaryl urea Relative symmetry with electronegativity Antiallergic activity Antigen-induced pulmonary inflammation |
| title | “Relative symmetry with electronegativity of different key-groups” strategy for MRGPRX2 antagonist design and its effect on antigen-induced pulmonary inflammation |
| title_full | “Relative symmetry with electronegativity of different key-groups” strategy for MRGPRX2 antagonist design and its effect on antigen-induced pulmonary inflammation |
| title_fullStr | “Relative symmetry with electronegativity of different key-groups” strategy for MRGPRX2 antagonist design and its effect on antigen-induced pulmonary inflammation |
| title_full_unstemmed | “Relative symmetry with electronegativity of different key-groups” strategy for MRGPRX2 antagonist design and its effect on antigen-induced pulmonary inflammation |
| title_short | “Relative symmetry with electronegativity of different key-groups” strategy for MRGPRX2 antagonist design and its effect on antigen-induced pulmonary inflammation |
| title_sort | relative symmetry with electronegativity of different key groups strategy for mrgprx2 antagonist design and its effect on antigen induced pulmonary inflammation |
| topic | MRGPRX2 Antagonist Diaryl urea Relative symmetry with electronegativity Antiallergic activity Antigen-induced pulmonary inflammation |
| url | http://www.sciencedirect.com/science/article/pii/S2211383524004568 |
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