Discovery of Potent Antiallergic Agents Based on an <i>o</i>-Aminopyridinyl Alkynyl Scaffold.
Xie Z, Xiang C, Li X, Fan C, Chen T, Liu M, Ma Y, Bai F, Tang W, Hu Y.
Effective therapeutic agents are highly desired for immune-mediated allergic diseases. Herein, we report the design, synthesis, and structure-activity relationship of an <i>o</i>-aminopyridinyl alkyne series as novel orally bioavailable antiallergic agents, which was identified through phenotypic screening. Compound optimization yielded a highly potent compound <b>36</b>, which effectively suppressed mast cell degranulation in a dose-dependent manner (IC<sub>50</sub>, 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, <b>36</b> 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 <b>36</b>. Compound <b>36</b> may serve as a new valuable lead compound for future antiallergic drug discovery.