基于药效团模型的新结构CCR2小分子拮抗剂的设计和合成
收稿日期: 2015-04-30
网络出版日期: 2015-05-15
基金资助
项目受国家自然科学基金(Nos. 81325020, 81361120410, 81321092)资助.
Pharmacophore Model-based Design and Synthesis of New Structure Small Molecule CCR2 Inhibitors
Received date: 2015-04-30
Online published: 2015-05-15
Supported by
Supporting information for this article is available free of charge via the Internet at http://sioc-journal.cn.Project supported by the National Natural Science Foundation of China (Nos. 81325020, 81361120410 and 81321092).
趋化因子受体CCR2已被证实可作为许多重要疾病的药物设计靶标, 如关节炎、多发性硬化症、动脉粥样硬化、糖尿病和肿瘤等. 我们运用基于药效团模型的优势碎片重组策略, 设计合成了11个新结构化合物. 分子水平的CCR2受体拮抗活性测试显示, 具有3-氨基环戊烷甲酰氨甲基酰胺骨架的化合物具有很好的抑制活性(1a, IC50=25 nmol/L). 进一步的构效关系研究表明, 左侧3-氨基上的取代基以脂肪环和小体积的芳香环为优选. 发现了有进一步优化价值的CCR2抑制剂新骨架, 初步构效关系研究也为进一步结构优化提供了有益的结构信息.
关键词： 趋化因子受体CCR2; 小分子拮抗剂; 药效团; 3-氨基环戊烷甲酰氨甲基酰胺
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 . DOI: 10.6023/A15040296
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.
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