Convenient Diaryl Ureas as Promising Anti-pseudo-allergic Agents

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 (IC50) 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.