a 中国科学院受体结构与功能重点实验室 中国科学院上海药物研究所 上海 201203;
b 中国科学院食品安全重点实验室 中国科学院上海营养科学研究所 上海 200031
Pharmacophore Model-based Design and Synthesis of New Structure Small Molecule CCR2 Inhibitors
Qin Lihuaia, Li Xiaoguangb, Wang Zhilonga, Yao Wenbob, Wang Huib, Xie Xina, Long Yaqia
a CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203;
b CAS Key Laboratory of Food Safety, Shanghai Institute of Nutrition Science, Chinese Academy of Sciences, Shanghai 200031
Chemokine receptor CCR2 is a member of the seven-transmembrane G-protein-coupled receptor superfamily, and is predominantly expressed on monocytes and macrophages. The interaction of the chemokine CCL2 with the CCR2 plays an important role in the recruitment of monocytes, natural killer cells, dendritic cells and T-lymphocytes. Recent studies have linked the CCL2/CCR2 axis to various inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, atherosclerosis, diabetes and even cancer. Thus, small molecule antagonists which can block the binding of CCR2 and CCL2 represent new therapeutic interventions of the inflammation-related diseases. By comprehensively analyzing the structures of the literature-reported potent CCR2 antagonists, we concluded a pharmacophore model for CCR2 inhibition, including a basic amino center, a hydrophobic aromatic ring on the right-hand side, and an amide group which serves as a hydrogen bond acceptor and a hydrogen bond donor. Then we performed the lead deconstruction and pharmacophore model-based privileged fragment reassembly strategy to discover new scaffold small molecule CCR2 inhibitors. The lead-like privileged scaffolds of α-alkyl-γ-aminobutanamide and glycinamide were selected to combine with novel aromatic moiety and amide portion, delivering 3 classes of new structure CCR2 inhibitors. Total 11 compounds were designed and synthesized via a facile convergent synthetic procedure. The CCR2 antagonism activity evaluation revealed that N-(3-aminocyclopentane- carboxamido)methyl)benzamide was an active scaffold (exemplified by 1a, IC50=25 nmol/L). The preliminary structure- activity relationship study indicated that the basic amino group and the lipophilic aliphatic moiety and small size aromatic group are important for the interaction with CCR2 protein. The replacement of the basic amino group with an amide would lead to the significant loss of the activity. This work provides a promising new structure CCR2 inhibitor and useful SAR conclusions which will promote the further development of CCR2 inhibitor into drug candidate.
秦立怀, 李晓光, 王志龙, 姚文博, 王慧, 谢欣, 龙亚秋. 基于药效团模型的新结构CCR2小分子拮抗剂的设计和合成[J]. 化学学报, 2015, 73(7): 679-684.
Qin Lihuai, Li Xiaoguang, Wang Zhilong, Yao Wenbo, Wang Hui, Xie Xin, Long Yaqi. Pharmacophore Model-based Design and Synthesis of New Structure Small Molecule CCR2 Inhibitors. Acta Chim. Sinica, 2015, 73(7): 679-684.
Huang, D. R.; Wang, J. T.; Kivisakk, P.; Rollins, B. J.; Ransohoff, R. M. J. Exp. Med. 2001, 193, 713.
Kinne, R. W.; Brauer, R.; Stuhlmuller, B.; Palombo-Kinne, E.; Burmester, G. R. Arthritis Res. Ther. 2000, 2, 189.
Fife, B. T.; Huffnagle, G. B.; Kuziel, W. A.; Karpus, W. J. J. Exp. Med. 2000, 192, 899.
Tracey, C. D.; William, A. K.; Tene, A. O.; Nobuyo, M. Atherosclerosis 1999, 143, 205.
Sullivan, T. J.; Miao, Z. H.; Zhao, B. N.; Ertl, L. S.; Wang, Y.; Krasinski, A.; Walters, M. J.; Powers, J. P.; Dairaghi, D. J.; Baumgart, T.; Seitz, L. C.; Berahovich, R. D.; Schall, T. J.; Jaen, J. C. Metabolism 2013, 62, 1623.
Conti, I.; Rollins, B. J. Semin. Cancer Biol. 2004, 14, 149.
(a) Carter, P. H. Expert Opin. Ther. Patents 2013, 23, 549;
Xia, M.; Sui, Z. Expert Opin. Ther. Patents 2009, 19, 295.
Struthers, M.; Pasternak, A. Curr. Top. Med. Chem. 2010, 10, 1278.
Xue, C.-B.; Zhang, C.-S.; Feng, H.; Xia, M. US 20060020133 A1, 2006 [Chem. Abstr. 2005, 144, 108363].
Yeh, V. S. C.; Kurukulasuriya, R.; Kerdesky, F. A. Org. Lett. 2006, 8, 3963.
Vilums, M.; Zweemer, A. J. M.; Yu, Z.; de Vries, H.; Hillger, J. M.; Wapenaar, H.; Bollen, I. A. E.; Barmare, F.; Gross, R.; Clemens, J.; Krenitsky, P.; Brussee, J.; Stamos, D.; Saunders, J.; Heitman, L. H.; Ijzerman, A. P. J. Med. Chem. 2013, 56, 7706.