Discovery of Potent Antiallergic Agents Based on an o -Aminopyridinyl Alkynyl Scaffold.

Effective therapeutic agents are highly desired for immune-mediated allergic diseases. Herein, we report the design, synthesis, and structure-activity relationship of an o -aminopyridinyl alkyne series as novel orally bioavailable antiallergic agents, which was identified through phenotypic screening. Compound optimization yielded a highly potent compound 36 , which effectively suppressed mast cell degranulation in a dose-dependent manner (IC ₅₀ , 2.54 nM for RBL-2H3 cells; 48.28 nM for peritoneal mast cells (PMCs)) with a good therapeutic index. It also regulated the activation of FcεRI-mediated downstream signaling proteins in IgE/Ag-stimulated RBL-2H3 cells. In addition, 36 exhibited excellent in vivo pharmacokinetic properties and antiallergic efficacy in both passive systemic anaphylaxis (PSA) and house dust mite (HDM)-induced murine models of pulmonary allergic inflammation. Furthermore, preliminary analysis of the kinases profile identified Src-family kinases as potential targets for 36 . Compound 36 may serve as a new valuable lead compound for future antiallergic drug discovery.