Design and synthesis of a series of pyrido[2,3-d]pyrimidine derivatives as CCR4 antagonists.
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.
School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
Hongwei
H
Gong
Hui
H
Qi
Wei
W
Sun
Yang
Y
Zhang
Dan
D
Jiang
Junhai
J
Xiao
Xiaohong
X
Yang
Ying
Y
Wang
Song
S
Li
D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000276:immunology; D065631:Rhinitis, Allergic; D012221:Rhinitis, Allergic, Perennial / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology
D018926:Anti-Allergic Agents; D011743:Pyrimidines; D054398:Receptors, CCR4