Design and synthesis of a series of pyrido[2,3-d]pyrimidine derivatives as CCR4 antagonists

• Published in: Molecules (Basel, Switzerland) Vol. 17; no. 8; pp. 9961 - 9970
• Main Authors: Gong, Hongwei, Qi, Hui, Sun, Wei, Zhang, Yang, Jiang, Dan, Xiao, Junhai, Yang, Xiaohong, Wang, Ying, Li, Song
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20.08.2012; MDPI
• Subjects: Animals; Anti-Allergic Agents - administration & dosage; Anti-Allergic Agents - chemistry; Anti-Allergic Agents - pharmacology; Asthma; CC chemokine receptor 4 (CCR4) antagonists; Cell Line; Chemokines; Chemotaxis - drug effects; CKLF1; Design; Female; Humans; Immunology; Inflammation; inflammatory disease; Ligands; Lungs; MDC; Mice; Pyrimidines - administration & dosage; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Receptors, CCR4 - antagonists & inhibitors; Receptors, CCR4 - immunology; Rhinitis; Rhinitis, Allergic; Rhinitis, Allergic, Perennial - chemically induced; Rhinitis, Allergic, Perennial - drug therapy; Rhinitis, Allergic, Perennial - immunology; TARC; Thymus gland; Beijing China; China
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules17089961

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.