Design and Synthesis of a Series of Pyrido[2,3-d]pyrimidine Derivatives as CCR4 Antagonists

Hongwei Gong,Hui Qi,Song Li,Xiaohong Yang,Dan Jiang,Wei Sun,Yang Zhang,Junhai Xiao,Ying Wang

doi:10.3390/molecules17089961

Hongwei Gong, Hui Qi + Show 7 more

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https://doi.org/10.3390/molecules17089961

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Abstract

A series of pyrido[2,3-d]pyrimidine derivatives were designed and synthesized based on known CC chemokine receptor 4 (CCR4) antagonists. The activities of all the newly synthesized compounds were evaluated using a chemotaxis inhibition assay. Compound 6b was proven to be a potent CCR4 antagonist that can block cell chemotaxis induced by macrophage-derived chemokine (MDC), thymus and activation regulated chemokine (TARC), and CKLF1, the natural ligands of CCR4. In addition, compound 6b is more effective than budesonide in the murine rhinitis model. The intravenous injection LD50 of compound 6b is 175 mg/kg and the oral LD50 is greater than 2,000 mg/kg.

Highlights

CC chemokine receptor 4 (CCR4) is a pivotal factor in the development of allergic inflammations, such as asthma, dermatitis, and rhinitis [1]
Through the chemotaxis of the three ligands of CCR4, the Th2 cells are attracted to the sites of allergic inflammation
The number of macrophage-derived chemokine (MDC), thymus and activation regulated chemokine (TARC), and CCR4-expressing T cells is increased in asthmatic lungs and airways

Summary

Introduction

CC chemokine receptor 4 (CCR4) is a pivotal factor in the development of allergic inflammations, such as asthma, dermatitis, and rhinitis [1]. It consists of a seven-transmembrane G-protein-coupled receptor that is selectively expressed on Th2 cell membranes. The number of MDC, TARC, and CCR4-expressing T cells is increased in asthmatic lungs and airways. The CCR4 blocking antibody attenuates airway eosinophilia and goblet cell hyperplasia and diminishes IgE synthesis and bronchial hyperreactivity [5]. Like the CCR4 antibody, the special Ab against TARC and MDC can reduce airway eosinophilia and hyperresponsiveness in asthmatic mice elicited by OVA [6,7].

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