Pharmacophore Model-based Design and Synthesis of New Structure Small Molecule CCR2 Inhibitors
文献类型：期刊论文
| 作者 | Qin Lihuai1; Li Xiaoguang2; Wang Zhilong1; Yao Wenbo2; Wang Hui2; Xie Xin1 ; Long Yaqiu1
|
| 刊名 | ACTA CHIMICA SINICA
 |
| 出版日期 | 2015-07-15 |
| 卷号 | 73期号:7页码:679-684 |
| 关键词 | chemokine receptor CCR2 small molecule antagonist pharmacophore N-(3-aminocyclopentanecarbox-amido)methyl)benzamide |
| ISSN号 | 0567-7351 |
| DOI | 10.6023/A15040296 |
| 文献子类 | Article |
| 英文摘要 | 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 alpha-alkyl-gamma-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. |
| WOS关键词 | CHEMOKINE RECEPTOR 2 ; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS ; MONOCYTE CHEMOATTRACTANT PROTEIN-1 ; EFFICIENT SYNTHESIS ; ANTAGONISTS ; DISCOVERY ; POTENT |
| 资助项目 | National Natural Science Foundation of China[81325020] ; National Natural Science Foundation of China[81361120410] ; National Natural Science Foundation of China[81321092] |
| WOS研究方向 | Chemistry |
| 语种 | 中文 |
| CSCD记录号 | CSCD:5502849 |
| WOS记录号 | WOS:000360199200003 |
| 出版者 | SCIENCE PRESS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276466]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Qin Lihuai |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Nutr Sci, CAS Key Lab Food Safety, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Qin Lihuai,Li Xiaoguang,Wang Zhilong,et al. Pharmacophore Model-based Design and Synthesis of New Structure Small Molecule CCR2 Inhibitors[J]. ACTA CHIMICA SINICA,2015,73(7):679-684. |
| APA | Qin Lihuai.,Li Xiaoguang.,Wang Zhilong.,Yao Wenbo.,Wang Hui.,...&Long Yaqiu.(2015).Pharmacophore Model-based Design and Synthesis of New Structure Small Molecule CCR2 Inhibitors.ACTA CHIMICA SINICA,73(7),679-684. |
| MLA | Qin Lihuai,et al."Pharmacophore Model-based Design and Synthesis of New Structure Small Molecule CCR2 Inhibitors".ACTA CHIMICA SINICA 73.7(2015):679-684. |
入库方式： OAI收割
来源：上海药物研究所
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