2. Academic Validation
  3. Discovery of Potent Antiallergic Agents Based on an o-Aminopyridinyl Alkynyl Scaffold

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

  • J Med Chem. 2021 Sep 23;64(18):13588-13603. doi: 10.1021/acs.jmedchem.1c00976.
Zhicheng Xie 1 2,  Caigui Xiang 3 2,  Xin Li 1 2,  Chen Fan 3,  Taiwen Chen 1 2,  Moting Liu 3,  Yanjie Ma 1,  Fang Bai 3,  Wei Tang 3 2,  Youhong Hu 1 2 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu-Chong-Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
  • 3 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China.
PMID: 34476950 DOI: 10.1021/acs.jmedchem.1c00976
Abstract

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 (IC50, 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.

Figures
Products