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).
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.
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[J]. Acta Chimica Sinica, 2015 , 73(7) : 679 -684 . DOI: 10.6023/A15040296
[1] Luster, A. D. N. Engl. J. Med. 1998, 338, 436.
[2] Huang, D. R.; Wang, J. T.; Kivisakk, P.; Rollins, B. J.; Ransohoff, R. M. J. Exp. Med. 2001, 193, 713.
[3] Kinne, R. W.; Brauer, R.; Stuhlmuller, B.; Palombo-Kinne, E.; Burmester, G. R. Arthritis Res. Ther. 2000, 2, 189.
[4] Fife, B. T.; Huffnagle, G. B.; Kuziel, W. A.; Karpus, W. J. J. Exp. Med. 2000, 192, 899.
[5] Tracey, C. D.; William, A. K.; Tene, A. O.; Nobuyo, M. Atherosclerosis 1999, 143, 205.
[6] 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.
[7] Conti, I.; Rollins, B. J. Semin. Cancer Biol. 2004, 14, 149.
[8] (a) Carter, P. H. Expert Opin. Ther. Patents 2013, 23, 549;
(b) Xia, M.; Sui, Z. Expert Opin. Ther. Patents 2009, 19, 295.
[9] Struthers, M.; Pasternak, A. Curr. Top. Med. Chem. 2010, 10, 1278.
[10] Xue, C.-B.; Feng, H.; Cao, G.; Huang, T.; Glenn, J.; Anand, R.; Meloni, D.; Zhang, K.; Kong, L.; Wang, A.; Zhang, Y.; Zheng, C.; Xia, M.; Chen, L.; Tanaka, H.; Han, Q.; Robinson, D. J.; Modi, D.; Storace, L.; Shao, L.; Sharief, V.; Li, M.; Galya, L. G.; Covington, M.; Scherle, P.; Diamond, S.; Emm, T.; Yeleswaram, S.; Contel, N.; Vaddi, K.; Newton, R.; Hollis, G.; Friedman, S.; Metcalf, B. ACS Med. Chem. Lett. 2011, 2, 450.
[11] (a) Fan, X.; Zhang, H.-S.; Chen, L.; Long, Y.-Q. Eur. J. Med. Chem. 2010, 45, 2827;
(b) Zhang, H.-S.; Feng, D.-Z.; Chen, L.; Long, Y.-Q. Bioorg. Med. Chem. Lett. 2010, 20, 2219.
[12] Xue, C.-B.; Zhang, C.-S.; Feng, H.; Xia, M. US 20060020133 A1, 2006 [Chem. Abstr. 2005, 144, 108363].
[13] Yeh, V. S. C.; Kurukulasuriya, R.; Kerdesky, F. A. Org. Lett. 2006, 8, 3963.
[14] 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.
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