School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi 710061, China.
Department of Pharmacy, 3201 Hospital Affiliated to Xi'an Jiaotong University, Hanzhong, Shaanxi 723000, China.
J Med Chem. 2022 Aug 11;65(15):10626-10637. doi: 10.1021/acs.jmedchem.2c00846. Epub 2022 Jul 24.
Allergic diseases are a group of allergen-induced unfavorable immune responses initiating various symptoms in different organs. Mas-related G protein-coupled receptor X2 (MRGPRX2) on mast cells has been reported to be responsible for immunoglobulin E (IgE)-independent immune diseases and allergic drug reactions and has therefore been a crucial drug target for the development of anti-pseudo-allergic agents. Considering the active structural features of MRGPRX2, we designed and synthesized a series of diaryl ureas (DPUs). DPUs exert promising potency for inhibiting β-hexosaminidase release in LAD2 cells with half-maximal inhibitory concentrations (IC) values of 2.51-0.62 μM, as well as favorable antilocal and systemic anaphylaxis in mice at a dosage of 10 mg/kg. MRGPRX2 is further revealed to participate in the anti-pseudo-allergic activity of DPUs by binding with electrophilic urea and trifluoromethyl substituents. In brief, these results highlight entities with powerful electrophilic substituents as a prospective therapeutic strategy for the treatment of IgE-independent disorders.
变应性疾病是一组过敏原诱导的不良免疫反应，可在不同器官引发各种症状。肥大细胞上的 Mas 相关 G 蛋白偶联受体 X2（MRGPRX2）已被报道负责免疫球蛋白 E（IgE）非依赖性免疫疾病和过敏药物反应，因此已成为开发抗假性过敏药物的关键药物靶点。鉴于 MRGPRX2 的活性结构特征，我们设计并合成了一系列二芳基脲（DPU）。DPU 对 LAD2 细胞中β-己糖胺酶释放的抑制作用具有良好的效力，半数最大抑制浓度（IC）值为 2.51-0.62 μM，在 10 mg/kg 剂量下对小鼠具有良好的抗局部和全身过敏反应作用。MRGPRX2 进一步通过与亲电脲和三氟甲基取代基结合参与 DPU 的抗假性过敏活性。总之，这些结果突出了具有强大亲电取代基的实体作为治疗 IgE 非依赖性疾病的有前途的治疗策略。
