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

1.
a Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China;
b Central Research Institute, Shanghai Pharmaceuticals Holding Co.
b Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201203, China

Corresponding author: Mao-Sheng Cheng, Jing-Kang Shen,
Received Date: 14 June 2013
Available Online: 23 October 2013

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.
- Cholesteryl ester transfer protein,
- CETP inhibitors,
- Pharmacophore,
- Virtual screening,
- Synthesis
1. [1]
  [1] H. Bays, E.A. Stein, Pharmacotherapy for dyslipidaemia - current therapies and future agents, Expert. Opin. Pharmacother. 4 (2003) 1901-1938.
2. [2]
  [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]
  [3] C.J. Fielding, P.E. Fielding, Molecular physiology of reverse cholesterol transport, J. Lipid Res. 36 (1995) 211-228.
4. [4]
  [4] P.J. Barter, K.A. Rye, Molecular mechanisms of reverse cholesterol transport, Curr. Opin. Lipidol. 7 (1996) 82-87.
5. [5]
  [5] G. Assmann, J.R. Nofer, Atheroprotective effects of high-density lipoproteins, Annu. Rev. Med. 54 (2003) 321-341.
6. [6]
  [6] A.R. Tall, Plasma cholesteryl ester transfer protein, J. Lipid Res. 34 (1993) 1255- 1274.
7. [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.
8. [8]
  [8] H. Bischoff, C. Schmeck, D. Schmidt, et al., Novel use of dioxocin-5-on derivatives, WO 2004039364.
9. [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.
10. [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.
11. [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.
12. [12]
  [12] G. Schmidt, R. Angerbauer, A. Brandes, et al., 2-Aryl-substituted pyridines, US5925645.
13. [13]
  [13] G. Schmidt, A. Brander, R. Angerbauer, et al., Preparation of tetrahydroquinolines and analogs as cholesteryl ester transfer protein inhibitors, US 6207671.
14. [14]
  [14] A. Brandes, M. Loegers, G. Schmidt, et al., Preparation of bicyclic condensed pyridines for treatment of hyperlipoproteinemia and arteriosclerosis, DE 19627430.
15. [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.
16. [16]
  [16] H. Gielen, S. Goldmann, J. Keldenich, et al., Preparation of spiro cyclobutyltetrahydroquinolinols as cholesterol ester transfer protein (CETP) inhibitors, WO 2003028727.
17. [17]
  [17] H. Bischoff, H. Gielen, V. Li, et al., Cycloalkyl substituted tetrahydro Chinoline derivatives and use there of medicaments, WO 20063828.
18. [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.
19. [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.
20. [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.
21. [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.
22. [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.
23. [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.
24. [24]
  [24] A. Ali, J.M. Napolitano, Q. Deng, et al., Preparation of cholesteryl ester transfer protein (CETP) inhibitors, WO 2006014413.
25. [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.
26. [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.
27. [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.
28. [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.
29. [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.
30. [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.
31. [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.
32. [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.
33. [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.
34. [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.
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