Design, Synthesis and SAR Study of Novel Trisubstituted Pyrimidine Amide Derivatives as CCR4 Antagonists

The design, synthesis and structure-activity relationship studies of some novel trisubstituted pyrimidine amide derivatives prepared as CCR4 antagonists are described. The activities of these compounds were evaluated by the CCR4-MDC chemotaxis inhibition assay. Compound 1, which we have previously reported as a potent antagonist of CCR4, was employed as the positive control. The results indicated that most of the synthesized compounds exhibited some chemotaxis inhibition activity against CCR4. Of these new compounds, compounds 6c, 12a and 12b, with IC50 values of 0.064, 0.077 and 0.069 μM, respectively, showed higher or similar activity compared with compound 1 (IC50 of 0.078 μM). These compounds provide a basis for further structural modifications. The systematic structure-activity relationship of these trisubstituted pyrimidine amide derivatives was discussed based on the obtained experimental data. The results from the SAR study may be useful for identifying more potent CCR4 antagonists.

[1]  Qi Hui,et al.  Design,Synthesis and Biological Activities of a Series of Piperazine Pyrimidine as CCR4 Antagonists , 2013 .

[2]  A. Asai,et al.  Internalization of CCR4 and Inhibition of Chemotaxis by K777, a Potent and Selective CCR4 Antagonist , 2013, Pharmacology.

[3]  W. A. Yeudall,et al.  Chemokines, chemokine receptors and the gastrointestinal system. , 2013, World journal of gastroenterology.

[4]  D. Greaves,et al.  CC Chemokine Receptors and Chronic Inflammation—Therapeutic Opportunities and Pharmacological Challenges , 2013, Pharmacological Reviews.

[5]  Hongwei Gong,et al.  Design and Synthesis of a Series of Pyrido[2,3-d]pyrimidine Derivatives as CCR4 Antagonists , 2012, Molecules.

[6]  S. Hodgson,et al.  Lead optimisation of the N1 substituent of a novel series of indazole arylsulfonamides as CCR4 antagonists and identification of a candidate for clinical investigation. , 2012, Bioorganic & medicinal chemistry letters.

[7]  R. Leurs,et al.  Pharmacological modulation of chemokine receptor function , 2012, British journal of pharmacology.

[8]  P. Workman,et al.  Preparation and evaluation of trisubstituted pyrimidines as phosphatidylinositol 3-kinase inhibitors. 3-Hydroxyphenol analogues and bioisosteric replacements. , 2011, Bioorganic & medicinal chemistry.

[9]  M. Yamashita,et al.  RS-1748, a novel CC chemokine receptor 4 antagonist, inhibits ovalbumin-induced airway inflammation in guinea pigs. , 2010, Biological & pharmaceutical bulletin.

[10]  P. Howarth,et al.  Chemokine Receptor 4 Plays a Key Role in T Cell Recruitment into the Airways of Asthmatic Patients , 2010, The Journal of Immunology.

[11]  J. Clardy,et al.  Synthesis and antiplasmodial activity of novel 2,4-diaminopyrimidines. , 2010, Bioorganic & medicinal chemistry letters.

[12]  A. Viola,et al.  Chemokines and their receptors: drug targets in immunity and inflammation. , 2008, Annual review of pharmacology and toxicology.

[13]  K. McIntyre,et al.  Core exploration in optimization of chemokine receptor CCR4 antagonists. , 2007, Bioorganic & medicinal chemistry letters.

[14]  A. Purandare,et al.  Antagonists of CCR4 as immunomodulatory agents. , 2006, Current topics in medicinal chemistry.

[15]  J. Wityak,et al.  Identification of chemokine receptor CCR4 antagonist. , 2005, Bioorganic & medicinal chemistry letters.

[16]  A. Proudfoot Chemokine receptors: multifaceted therapeutic targets , 2002, Nature Reviews Immunology.

[17]  R. Pawankar,et al.  Inducible Expression of a Th2-Type CC Chemokine Thymus- and Activation-Regulated Chemokine by Human Bronchial Epithelial Cells1 , 2000, The Journal of Immunology.

[18]  A. Wagner,et al.  Efficient and Regioselective 4‐Amino‐de‐chlorination of 2,4,6‐Trichloropyrimidine with N‐Sodium Carbamates. , 2000 .

[19]  P. Allavena,et al.  Differential Expression of Chemokine Receptors and Chemotactic Responsiveness of Type 1 T Helper Cells (Th1s) and Th2s , 1998, The Journal of experimental medicine.

[20]  S. Fricker,et al.  Chemokine receptor modeling: an interdisciplinary approach to drug design. , 2014, Future medicinal chemistry.