Anti-allergic compounds of o-aminopyridinealkynes discovered by Shanghai Institute of Medicine

Allergic disease is a chronic disease.
Common allergic diseases include food allergy, drug allergy, allergic rhinitis, asthma, urticaria, eczema, allergic conjunctivitis and atopic dermatitis, etc.
The main feature is that the body targets antigens.
Produce specific IgE antibodies
.
At present, the global prevalence of allergic diseases is 20%-30%, and it is increasing year by year
.
Due to the complex pathogenic factors of allergic diseases, the current anti-allergic therapy drugs mainly correct the imbalance of the body's immune system and inhibit allergic inflammation, such as commonly used glucocorticoid drugs, histamine/leukotriene receptor antagonists, but The above-mentioned drugs have shortcomings such as strong side effects, single target and low response rate
.
At present, the only treatment that can fundamentally control and inhibit allergic inflammation is antibody therapy.
For example, anti-IgE antibody (Omalizumab, etc.
) and anti-IL-5 antibody (Mepolizumab, etc.
) have been approved for marketing for some serious and uncontrollable conditions.
The treatment of patients with allergic diseases, but the therapy still has shortcomings such as long treatment cycle, poor patient compliance, and high cost
.
Therefore, the development of new anti-allergic small molecule drugs with strong anti-allergic activity and low adverse reactions has great clinical application value
.

In the early stage, Hu Youhong's group from Shanghai Institute of Materia Medica, Chinese Academy of Sciences developed a series of structurally characteristic diarylalkynyl small molecule kinase inhibitors, such as FGFR inhibitors (Eur.
J.
Med.
Chem.
, 2017,126:122-132.
), a novel anti-inflammatory CSF-1R selective inhibitor (J.
Med.
Chem.
, 2020,63(3):1397-1414.
)
.
On this basis, Hu Youhong's research group and Tang Wei's research group of the Institute of Pharmaceutical Sciences have conducted anti-allergic activity-oriented phenotypic screening of the representative compounds of the kinase library on the mast cell model, and found that kinase inhibitors have strong resistance.
Allergic effects, and through phenotypic screening to study the fine structure-activity relationship, a new type of potent anti-allergic compound was discovered
.
Among them, the representative compounds have significant anti-allergic activity in both RBL-2H3 and murine primary mast cells (PMC), and have a large therapeutic index (RBL-2H3: IC50 2.
54 nM, CC50 377.
4 nM; PMC: IC50 48.
3 nM, CC50 836.
1 nM)
.
In addition, the compound can significantly inhibit the related signal pathways of mast cell activation and sensitization, and has good PK properties
.
The in vivo efficacy shows that the compound has significant effects in passive systemic allergic reaction (PSA) and house dust mite-induced pulmonary allergic inflammation mouse models, with low toxicity; representative compounds have passed preliminary zymogram analysis and interacted with SFKs (Src family kinases) inhibitor SU6656 comparative experiments show that these compounds exert anti-allergic activity by inhibiting SFKs
.
This research provides new ideas for the development of new, safe and effective anti-allergic clinical treatment drugs
.

　　The above research results were published in the Journal of Medicinal Chemistry under the title "Discovery of Potent Antiallergic Agents Based on an o-Aminopyridinyl Alkynyl Scaffold" on September 3, 2021
.
Researcher Hu Youhong and Researcher Tang Wei from Shanghai Institute of Medicine are the co-corresponding authors of this article.
Doctoral student Xie Zhicheng in Hu Youhong's group and Xiang Caigui, doctoral student in Tang Wei's group are the co-first authors
.
The research was funded by the Shanghai Science and Technology Commission
.

　　Full text link: https://pubs.
acs.
org/doi/10.
1021/acs.
jmedchem.
1c00976

Figure 1 Research strategy

Figure 2 Preferred compounds have significant anti-allergic activity in vivo

(Contribution department: Hu Youhong's research group; Contributor: Xie Zhicheng)