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

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 <strong>6b</strong> 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 <strong>6b</strong> is more effective than budesonide in the murine rhinitis model. The intravenous injection LD₅₀ of compound <strong>6b</strong> is 175 mg/kg and the oral LD₅₀ is greater than 2,000 mg/kg.

Keywords

• CC chemokine receptor 4 (CCR4) antagonists
• CKLF1
• TARC
• MDC
• inflammatory disease