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Pharmacophore-based design, synthesis, and biological evaluation of novel 3-((3, 4-dichlorophenyl)(4-substituted benzyl)amino) propanamides as cholesteryl ester transfer protein (CETP) inhibitors

Dong-Mei Zhao ,  Wen-Yan Li ,  Yu-Fang Shi ,  Xu-Qiong Xiong ,  Shuai Song ,  Chen-Zhou Hao ,  Mao-Sheng Cheng ,  Jing-Kang Shen

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Citation:  Dong-Mei Zhao, Wen-Yan Li, Yu-Fang Shi, Xu-Qiong Xiong, Shuai Song, Chen-Zhou Hao, Mao-Sheng Cheng, Jing-Kang Shen. Pharmacophore-based design, synthesis, and biological evaluation of novel 3-((3, 4-dichlorophenyl)(4-substituted benzyl)amino) propanamides as cholesteryl ester transfer protein (CETP) inhibitors[J]. Chinese Chemical Letters, 2014, 25(2): 299-304. shu

Pharmacophore-based design, synthesis, and biological evaluation of novel 3-((3, 4-dichlorophenyl)(4-substituted benzyl)amino) propanamides as cholesteryl ester transfer protein (CETP) inhibitors

    • 通讯作者: Mao-Sheng Cheng,
    Jing-Kang Shen,
摘要: Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that plays an important role in decreasing high-density lipoprotein cholesterol (HDL-C) levels and increasing low-density lipoprotein cholesterol (LDL-C) levels. Inhibition of CETP may be a new therapy for treating atherosclerosis. Herein, we report the development of a ligand-based pharmacophore model and pharmacophore-based virtual screening of the ZINC/big-n-greasy database, leading to the identification of compound H-10 as a potential CETP inhibitor in vitro. Based on H-10, a series of 3-((3,4-dichlorophenyl)(4-substituted benzyl)amino) propanamides were designed, synthesized, and evaluated against CETP. Compound 4l was found to have the best activity, resulting in 85.0% inhibition of CETP at 10 μmol/L.

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    1. [1] H. Bays, E.A. Stein, Pharmacotherapy for dyslipidaemia - current therapies and future agents, Expert. Opin. Pharmacother. 4 (2003) 1901-1938.[1] H. Bays, E.A. Stein, Pharmacotherapy for dyslipidaemia - current therapies and future agents, Expert. Opin. Pharmacother. 4 (2003) 1901-1938.

    2. [2] R.A. Lange, M.L. Lindsey, HDL-cholesterol levels and cardiovascular risk: acCETPing the context, Eur. Heart J. 29 (2008) 2708-2709.[2] R.A. Lange, M.L. Lindsey, HDL-cholesterol levels and cardiovascular risk: acCETPing the context, Eur. Heart J. 29 (2008) 2708-2709.

    3. [3] C.J. Fielding, P.E. Fielding, Molecular physiology of reverse cholesterol transport, J. Lipid Res. 36 (1995) 211-228.[3] C.J. Fielding, P.E. Fielding, Molecular physiology of reverse cholesterol transport, J. Lipid Res. 36 (1995) 211-228.

    4. [4] P.J. Barter, K.A. Rye, Molecular mechanisms of reverse cholesterol transport, Curr. Opin. Lipidol. 7 (1996) 82-87.[4] P.J. Barter, K.A. Rye, Molecular mechanisms of reverse cholesterol transport, Curr. Opin. Lipidol. 7 (1996) 82-87.

    5. [5] G. Assmann, J.R. Nofer, Atheroprotective effects of high-density lipoproteins, Annu. Rev. Med. 54 (2003) 321-341.[5] G. Assmann, J.R. Nofer, Atheroprotective effects of high-density lipoproteins, Annu. Rev. Med. 54 (2003) 321-341.

    6. [6] A.R. Tall, Plasma cholesteryl ester transfer protein, J. Lipid Res. 34 (1993) 1255- 1274.[6] A.R. Tall, Plasma cholesteryl ester transfer protein, J. Lipid Res. 34 (1993) 1255- 1274.

    7. [7] P.J. Barter, J.J.P. Kastelein, Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease, J. Am. Coll. Cardiol. 47 (2006) 492-499.[7] P.J. Barter, J.J.P. Kastelein, Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease, J. Am. Coll. Cardiol. 47 (2006) 492-499.

    8. [8] H. Bischoff, C. Schmeck, D. Schmidt, et al., Novel use of dioxocin-5-on derivatives, WO 2004039364.[8] H. Bischoff, C. Schmeck, D. Schmidt, et al., Novel use of dioxocin-5-on derivatives, WO 2004039364.

    9. [9] D. Brückner, F.T. Hafner, V. Li, et al., Dibenzodioxocinones—a new class of CETP inhibitors, Bioorg. Med. Chem. Lett. 15 (2005) 3611-3614.[9] D. Brückner, F.T. Hafner, V. Li, et al., Dibenzodioxocinones—a new class of CETP inhibitors, Bioorg. Med. Chem. Lett. 15 (2005) 3611-3614.

    10. [10] R.C. Durley, M.L. Grapperhaus, M.A. Massa, et al., Discovery of chiral N,N-disubstituted trifluoro-3-amino-2-propanols as potent inhibitors of cholesteryl ester transfer protein, J. Med. Chem. 43 (2000) 4575-4578.[10] R.C. Durley, M.L. Grapperhaus, M.A. Massa, et al., Discovery of chiral N,N-disubstituted trifluoro-3-amino-2-propanols as potent inhibitors of cholesteryl ester transfer protein, J. Med. Chem. 43 (2000) 4575-4578.

    11. [11] H. Paulsen, C. Schmeck, A. Brandes, et al., Fluorine-substitution in cholesterylester transfer protein inhibitors (CETP-inhibitors): biology, chemistry, SAR, and properties, Chimia 58 (2004) 123-127.[11] H. Paulsen, C. Schmeck, A. Brandes, et al., Fluorine-substitution in cholesterylester transfer protein inhibitors (CETP-inhibitors): biology, chemistry, SAR, and properties, Chimia 58 (2004) 123-127.

    12. [12] G. Schmidt, R. Angerbauer, A. Brandes, et al., 2-Aryl-substituted pyridines, US5925645.[12] G. Schmidt, R. Angerbauer, A. Brandes, et al., 2-Aryl-substituted pyridines, US5925645.

    13. [13] G. Schmidt, A. Brander, R. Angerbauer, et al., Preparation of tetrahydroquinolines and analogs as cholesteryl ester transfer protein inhibitors, US 6207671.[13] G. Schmidt, A. Brander, R. Angerbauer, et al., Preparation of tetrahydroquinolines and analogs as cholesteryl ester transfer protein inhibitors, US 6207671.

    14. [14] A. Brandes, M. Loegers, G. Schmidt, et al., Preparation of bicyclic condensed pyridines for treatment of hyperlipoproteinemia and arteriosclerosis, DE 19627430.[14] A. Brandes, M. Loegers, G. Schmidt, et al., Preparation of bicyclic condensed pyridines for treatment of hyperlipoproteinemia and arteriosclerosis, DE 19627430.

    15. [15] J. Stoltefuss, M. Loegers, G. Schmidt, et al., 4-Heteroaryl-tetrahydroquinolines and their use as inhibitors of the cholesterin-ester transfer protein, WO 9914215.[15] J. Stoltefuss, M. Loegers, G. Schmidt, et al., 4-Heteroaryl-tetrahydroquinolines and their use as inhibitors of the cholesterin-ester transfer protein, WO 9914215.

    16. [16] H. Gielen, S. Goldmann, J. Keldenich, et al., Preparation of spiro cyclobutyltetrahydroquinolinols as cholesterol ester transfer protein (CETP) inhibitors, WO 2003028727.[16] H. Gielen, S. Goldmann, J. Keldenich, et al., Preparation of spiro cyclobutyltetrahydroquinolinols as cholesterol ester transfer protein (CETP) inhibitors, WO 2003028727.

    17. [17] H. Bischoff, H. Gielen, V. Li, et al., Cycloalkyl substituted tetrahydro Chinoline derivatives and use there of medicaments, WO 20063828.[17] H. Bischoff, H. Gielen, V. Li, et al., Cycloalkyl substituted tetrahydro Chinoline derivatives and use there of medicaments, WO 20063828.

    18. [18] L.F. Lee, K.C. Glenn, D.T. Connolly, et al., Preparation of pyridinecarboxylates and analogs as cholesteryl ester transfer protein inhibitors, WO 9941237.[18] L.F. Lee, K.C. Glenn, D.T. Connolly, et al., Preparation of pyridinecarboxylates and analogs as cholesteryl ester transfer protein inhibitors, WO 9941237.

    19. [19] G. Chang, T. Didiuk, J. Finneman, et al., Preparation of 1,2,4-substituted 1,2,3,4- tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as CETP inhibitors for the treatment of atherosclerosis and obesity, WO 200408540.[19] G. Chang, T. Didiuk, J. Finneman, et al., Preparation of 1,2,4-substituted 1,2,3,4- tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as CETP inhibitors for the treatment of atherosclerosis and obesity, WO 200408540.

    20. [20] Z. Jones, R. Groneberg, M. Drew, et al., Preparation of 1,2,3,4-tetrahydroquinoxaline derivatives as inhibitors of cholesteryl ester transfer protein (CETP), US 20050282812.[20] Z. Jones, R. Groneberg, M. Drew, et al., Preparation of 1,2,3,4-tetrahydroquinoxaline derivatives as inhibitors of cholesteryl ester transfer protein (CETP), US 20050282812.

    21. [21] C.T. Eary, Z.S. Jones, R.D. Groneberg, et al., Tetrazole and ester substituted tetrahydoquinoxalines as potent cholesteryl ester transfer protein inhibitors, Bioorg. Med. Chem. Lett. 17 (2007) 2608-2613.[21] C.T. Eary, Z.S. Jones, R.D. Groneberg, et al., Tetrazole and ester substituted tetrahydoquinoxalines as potent cholesteryl ester transfer protein inhibitors, Bioorg. Med. Chem. Lett. 17 (2007) 2608-2613.

    22. [22] A. Conte-Mayweg, H. Kuehne, M. Cyrille, et al., Preparation of indole, indazole or indoline derivatives as cholesterol ester-exchanging protein inhibitors, WO 2006013048.[22] A. Conte-Mayweg, H. Kuehne, M. Cyrille, et al., Preparation of indole, indazole or indoline derivatives as cholesterol ester-exchanging protein inhibitors, WO 2006013048.

    23. [23] C.F. Thompson, A. Ali, N. Quraishi, et al., Discovery of substituted biphenyl oxazolidinone inhibitors of cholesteryl ester transfer protein, Med. Chem. Lett. 2 (2011) 424-427.[23] C.F. Thompson, A. Ali, N. Quraishi, et al., Discovery of substituted biphenyl oxazolidinone inhibitors of cholesteryl ester transfer protein, Med. Chem. Lett. 2 (2011) 424-427.

    24. [24] A. Ali, J.M. Napolitano, Q. Deng, et al., Preparation of cholesteryl ester transfer protein (CETP) inhibitors, WO 2006014413.[24] A. Ali, J.M. Napolitano, Q. Deng, et al., Preparation of cholesteryl ester transfer protein (CETP) inhibitors, WO 2006014413.

    25. [25] J.A. Sikorski, R.C. Durley, M.A. Massa, et al., Preparation of N-benzyl-N-phenylamino alcohols as cholesteryl ester transfer protein activity inhibitors, US 6482862.[25] J.A. Sikorski, R.C. Durley, M.A. Massa, et al., Preparation of N-benzyl-N-phenylamino alcohols as cholesteryl ester transfer protein activity inhibitors, US 6482862.

    26. [26] R.C. Durley, M.L. Grapperhaus, B.S. Hickory, et al., Chiral N,N-disubstituted trifluoro- 3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein, J. Med. Chem. 45 (2002) 3891-3904.[26] R.C. Durley, M.L. Grapperhaus, B.S. Hickory, et al., Chiral N,N-disubstituted trifluoro- 3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein, J. Med. Chem. 45 (2002) 3891-3904.

    27. [27] M. Kori, K. Hamamura, H. Fuse, et al., Preparation of aminoethanol derivatives as cholesteryl ester transfer protein inhibitors for treatment of hyperlipidemia, WO 2002059077.[27] M. Kori, K. Hamamura, H. Fuse, et al., Preparation of aminoethanol derivatives as cholesteryl ester transfer protein inhibitors for treatment of hyperlipidemia, WO 2002059077.

    28. [28] D.E. Epps, K.A. Greenlee, J.S. Harris, et al., Kinetics and inhibition of lipid exchange catalyzed by plasma cholesteryl ester transfer protein (lipid transfer protein), Biochemistry 34 (1995) 12560-12569.[28] D.E. Epps, K.A. Greenlee, J.S. Harris, et al., Kinetics and inhibition of lipid exchange catalyzed by plasma cholesteryl ester transfer protein (lipid transfer protein), Biochemistry 34 (1995) 12560-12569.

    29. [29] D.T. Connolly, E.S. Krul, D. Heuvelman, K.C. Glenn, Inhibition of cholesteryl ester transfer protein by apolipoproteins, lipopolysaccharides, and cholesteryl sulfate, Biochim. Biophys. Acta 1304 (1996) 145-160.[29] D.T. Connolly, E.S. Krul, D. Heuvelman, K.C. Glenn, Inhibition of cholesteryl ester transfer protein by apolipoproteins, lipopolysaccharides, and cholesteryl sulfate, Biochim. Biophys. Acta 1304 (1996) 145-160.

    30. [30] J.C. Lee, S.J. Coval, J. Clardy, A cholesteryl ester transfer protein inhibitor from an insect-associated fungus, J. Antibiot. 49 (1996) 693-696.[30] J.C. Lee, S.J. Coval, J. Clardy, A cholesteryl ester transfer protein inhibitor from an insect-associated fungus, J. Antibiot. 49 (1996) 693-696.

    31. [31] D.H. Hua, X.D. Huang, Y. Chen, et al., Total syntheses of (+)-chloropuupehenone and (+)-chloropuupehenol and their analogues and evaluation of their bioactivities, J. Org. Chem. 69 (2004) 6065-6078.[31] D.H. Hua, X.D. Huang, Y. Chen, et al., Total syntheses of (+)-chloropuupehenone and (+)-chloropuupehenol and their analogues and evaluation of their bioactivities, J. Org. Chem. 69 (2004) 6065-6078.

    32. [32] W.Y. Li, X.Q. Xiong, D.M. Zhao, et al., Quinoline-3-carboxamide derivatives as potential cholesteryl ester transfer protein inhibitors, Molecules 17 (2012) 5497- 5507.[32] W.Y. Li, X.Q. Xiong, D.M. Zhao, et al., Quinoline-3-carboxamide derivatives as potential cholesteryl ester transfer protein inhibitors, Molecules 17 (2012) 5497- 5507.

    33. [33] J. Böstrom, J.R. Greenwood, J. Gottfries, Assessing the performance of OMEGA with respect to retrieving bioactive conformations, J. Mol. Graph. Model. 21 (2003) 449-462.[33] J. Böstrom, J.R. Greenwood, J. Gottfries, Assessing the performance of OMEGA with respect to retrieving bioactive conformations, J. Mol. Graph. Model. 21 (2003) 449-462.

    34. [34] S. Renner, C.H. Schwab, J. Gasteiger, G. Schneider, Impact of conformational flexibility on three-dimensional similarity searching using correlation vectors, J. Chem. Inf. Model. 46 (2006) 2324-2332.[34] S. Renner, C.H. Schwab, J. Gasteiger, G. Schneider, Impact of conformational flexibility on three-dimensional similarity searching using correlation vectors, J. Chem. Inf. Model. 46 (2006) 2324-2332.

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  • 收稿日期:  2013-06-14
  • 网络出版日期:  2013-10-23
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