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Molecules 2012, 17(8), 9961-9970; doi:10.3390/molecules17089961

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

1
School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China
2
Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China
3
School of Public Health, Jilin University, Changchun 130021, China
4
Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Science Center, Beijing 100191, China
*
Authors to whom correspondence should be addressed.
Received: 26 June 2012 / Revised: 6 August 2012 / Accepted: 13 August 2012 / Published: 20 August 2012
(This article belongs to the Section Medicinal Chemistry)
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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. View Full-Text
Keywords: CC chemokine receptor 4 (CCR4) antagonists; CKLF1; TARC; MDC; inflammatory disease CC chemokine receptor 4 (CCR4) antagonists; CKLF1; TARC; MDC; inflammatory disease
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Gong, H.; Qi, H.; Sun, W.; Zhang, Y.; Jiang, D.; Xiao, J.; Yang, X.; Wang, Y.; Li, S. Design and Synthesis of a Series of Pyrido[2,3-d]pyrimidine Derivatives as CCR4 Antagonists. Molecules 2012, 17, 9961-9970.

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