Oral cholesteryl ester transfer protein (CETP) inhibitors: A potential new approach for treating coronary artery disease

Journal of Medicinal Chemistry

Volumn 49, Issue 1, 2006, Pages 1-22

  Sikorski, James A ^a  

^a AtheroGenics Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,2,3,4 TETRAHYDROQUINOLINE DERIVATIVE; 2 METHYLPROPANETHIOIC ACID S [2 [1 (2 ETHYLBUTYL)CYCLOHEXYLCARBOXAMIDO]PHENYL] ESTER; 5,6,7,8 TETRAHYDROQUINOLINE DERIVATIVE; CHOLESTEROL ESTER TRANSFER PROTEIN INHIBITOR; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; SC 591; SC 71952; SC 75744; TORCETRAPIB; UNCLASSIFIED DRUG;

ATHEROSCLEROSIS; CARDIOVASCULAR RISK; CHOLESTEROL TRANSPORT; CORONARY ARTERY DISEASE; DRUG MECHANISM; DRUG STRUCTURE; HUMAN; IC 50; NONHUMAN; REVIEW;

ADMINISTRATION, ORAL; ANIMALS; CARRIER PROTEINS; CHOLESTEROL ESTER TRANSFER PROTEINS; CORONARY ARTERIOSCLEROSIS; GLYCOPROTEINS; HUMANS; MOLECULAR STRUCTURE; PROPANOLAMINES; QUINOLINES; STRUCTURE-ACTIVITY RELATIONSHIP; SULFHYDRYL COMPOUNDS; TETRAHYDRONAPHTHALENES;

EID: 30444432694     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm058224l     Document Type: Review

References (215)

1. Bruce, C.; Chouinard, R. A., Jr.; Tall, A. R. Plasma lipid transfer proteins, high-density lipoproteins, and reverse cholesterol transport. Annu. Rev. Nutr. 1998, 18, 297-330.
2. (a) Sikorski, J. A.; Connolly, D. T. The discovery of new cholesteryl ester transfer protein inhibitors. Curr. Opin. Drug Discovery Dev. 2001, 4, 602-613.
3. (b) Sikorski, J. A.; Glenn, K. C. Cholesteryl ester transfer protein as a potential therapeutic target to improve the HDL to LDL cholesterol ratio. Annu. Rep. Med. Chem. 2000, 35, 251-260.
4. (c) Ruggeri, R. B. Cholesteryl ester transfer protein: pharmacological inhibition for the modulation of plasma cholesterol levels and promising target for the prevention of atherosclerosis. Curr. Top. Med. Chem. 2005, 5, 257-264.
5. (d) Clark, R. W.; Chang, G.; Didiuk, M. T. Agents for the inhibition of cholesteryl ester transfer protein (CETP) and prospects for the future treatments of atherosclerosis. Curr. Med. Chem.: Immunol., Endocr. Metab. Agents 2005, 5, 339-360.
6. (a) Le Goff, W.; Guerin, M.; Chapman, M. J. Pharmacological modulation of cholesteryl ester transfer protein, a new target in atherogenic dyslipidemia. Pharmacol. Ther. 2004, 101, 17-38.
7. (b) de Grooth, G. J.; Klerkx, A. H. E. M.; Stroes, E. S. G.; Stalenhoef, A. F. H.; Kastelein, J. J. P.; Kuivenhoven, J. A. A review of CETP and its relation to atherosclerosis. J. Lipid Res. 2004, 45, 1967-1974.
8. (c) Barter, P. J.; Brewer, H. B.; Chapman, J.; Hennekens, C. H.; Rader, D. J.; Tall, A. R. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler., Thromb., Vasc. Biol. 2003, 23, 160-167.
9. (d) Stein, O.; Stein, Y. Lipid transfer proteins (LTP) and atherosclerosis. Atherosclerosis 2005, 178, 217-230.
10. (a) Inazo, A.; Mabuchi, H. Therapeutic implications of cholesteryl ester transfer protein inhibitors in hyperlipidemia and low high-density lipoprotein-cholesterolemia. Curr. Opin. Invest. Drugs 2003, 4, 291-297.
11. (b) Chauhan, V.; Walter, S.; Nguyen, A. T.; Milne, R. Cholesteryl ester transfer protein: structure, function and role in atherosclerosis. Recent Rex. Dev. Lipids 2001, 5, 37-45.
12. (c) Inazo, A.; Koizumi, J.; Mabuchi, H. Cholesteryl ester transfer protein and atherosclerosis. Curr. Opin. Lipidol. 2000, 11, 389-396.
13. (d) Hirano, K.-I.; Yamashita, S.; Matsuzawa, Y. Pros and cons of inhibiting cholesteryl ester transfer protein. Curr. Opin. Lipidol. 2000, 11, 589-596.
14. (e) Parini, P.; Rudel, L. L. Is there a need for cholesteryl ester transfer protein inhibition? Arterioscler., Thromb., Vasc. Biol. 2003, 23, 374-375.
15. (f) Watts, G. F. The yin and yang of cholesteryl ester transfer protein and atherosclerosis. Clin. Sci. 2002, 103, 595-597.
16. Lagrost, L. Relationship of the cholesteryl ester transfer protein (CETP) to atherosclerosis. Adv. Vasc. Biol. 1999, 5, 217-231.
17. (a) Linsel-Nitschke, P.; Tall, A. R. HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nat. Rev. Drug Discovery 2005, 4, 193-205.
18. (b) Wang, M.; Briggs, M. R. HDL: the metabolism, function and therapeutic importance. Chem. Rev. 2004, 104, 119-137.
19. (c) Assmann, G.; Noter, J.-R. Atheroprotective effects of high-density lipoproteins. Annu. Rev. Med. 2003, 54, 321-341.
20. (d) Rader, D. J. High-density lipoproteins and atherosclerosis. Am. J. Cardiol. 2002, 90, 62i-70i.
21. (e) Lund-Katz, S.; Liu, L.; Thuahnai, S. T.; Phillips, M. C. High density lipoprotein structure. Front. Biosci. 2003, 8, d1044-d1054.
22. (f) Schmitz, G.; Langmann, T. High-density lipoproteins and ATP-binding cassette transporters as targets for cardiovascular drug therapy. Curr. Opin. Invest. Drugs 2005, 6, 907-919.
23. de Grooth, G. J.; Kuivenhoven, J. A.; Stalenhoef, A. F. H.; de Graaf, J.; Zwinderman, A. H.; Posma, J. L.; van Tol, A.; Kastelein, J. J. P. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: A randomized phase II dose-response study. Circulation 2002, 105, 2159-2165.
24. (a) Clark, R. W.; Sutfin, T. A.; Ruggeri, R. B.; Willauer, A. T.; Sugarman, E. D.; Magnus-Aryitey, G.; Cosgrove, P. G.; Sand, T. M.; Wester, R. T.; Williams, J. A.; Perlman, M. E.; Bamberger, M. J. Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein. Arterioscler., Thromb., Vasc. Biol. 2004, 24, 490-497.
25. (b) Brousseau, M. E.; Schaefer, E. J.; Wolfe, M. L.; Bloedon, L. T.; Digenio, A. G.; Clark, R. W.; Mancuso, J. P.; Rader, D. J. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N. Engl. J. Med. 2004, 350, 1505-1515.
26. (a) Loscalzo, J., Ed. Molecular Mechanisms of Atherosclerosis; Taylor and Francis: London, U.K., 2005.
27. (b) Hansson, G. K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 2005, 352, 1685-1695.
28. (c) Libby, P.; Ridker, P. M.; Maseri, A. Inflammation and atherosclerosis. Circulation 2002, 105, 1135-1143.
29. (d) Ross, R. Atherosclerosis, an inflammatory disease. N. Engl. J. Med. 1999, 340, 115-126.
30. (a) Mehta, J. L., Ed. Statins: Understanding Clinical Use; Saunders: Philadelphia. PA, 2004.
31. (b) Evans, M.; Roberts, A.; Davies, S.; Rees, A. Medical lipid-regulating therapy: Current evidence, ongoing trials and future developments. Drugs 2004, 64, 1181-1196.
32. Clader, J. W. The Discovery of ezetimibe: a view from outside the receptor. J. Med. Chem. 2004, 47, 1-9.
33. (a) Pederson, T. R.; Olsson, A. G.; Faergeman, O.; Kjekshus, J.; Wedel, H.; Berg, K.; Wilhelmsen, L.; Haghfelt, T.; Thorgeirsson, G.; Pyorala, K.; Miettinen, T.; Christophersen, B.; Tobert, J. A.; Musliner, T. A.; Cook, T. J. Lipoprotein changes and reduction in the incidence of major coronary heart disease in the Scandanavian simvistatin survival study (4S). Circulation 1998, 97, 1453-1460.
34. (b) The West of Scotland Coronary Prevention Study Group. Influence of pravaststin and plasma lipids on clinical events in the West of Scotland coronary prevention study (WOSCOPS). Circulation 1998, 97, 1440-1445.
35. (a) Knopp, R. H. Drug treatment of lipid disorders. N. Engl. J. Med. 1999, 34, 498-511.
36. (b) Grundy, S. M. Statin trials and goals of cholesterol-lowering therapy. Circulation 1998, 97, 1436-1439.
37. Genest, J. J.; McNamara, J. R.; Salem, D. N.; Schaefer, E. J. Prevalence of risk factors in men with coronary artery disease. Am. J. Cardiol. 1991, 67, 1185-1189.
38. (a) Kannel, W. B. Range of serum cholesterol values in the population developing coronary artery disease. Am. J. Cardiol. 1995, 76, 69c-77c.
39. (b) Burchfiel, C. M.; Laws, A.; Benfante, R.; Goldberg, R. J.; Hwang, L.-J.; Chiu, D.; Rodriguez, B. L.; Curb, J. D.; Sharp, D. S. Combined effects of HDL cholesterol, triglyceride, and total cholesterol concentrations on 18-year risk of atherosclerotic disease. Circulation 1995, 92, 1430-1436.
40. (c) Lamarche, B.; Despres, J.-P.; Moorjani, S.; Cantin, B.; Dagenais. G. R.; Lupien, P.-J. Triglycerides and HDL-cholesterol as risk factors for ischemic heart disease. Results from the Quebec cardiovascular study. Atherosclerosis 1996, 119, 235-245.
41. Executive summary of the third report of the NCEP expert panel on detection, evaluation and treatment of high blood cholesterol in adults. J. Am. Med. Assoc. 2001, 285, 2486-2497.
42. Wilson, P. W. F.; D'Agostino, R. B.; Levy, D.; Belanger, A. M.; Silbershatz, H.; Kannel, W. B. Prediction of coronary heart disease using risk factor categories. Circulation 1998, 97, 1837-1847.
43. Manninen, V.; Tenkanen, L.; Koskinen, P.; Huttunen, J. K.; Manttari, M.; Heinonen, O. P.; Frick, H. M. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki heart study. Implications for treatment. Circulation 1992, 85, 37-45.
44. Robins, S. J.; Collins, D.; Wittes, J. T.; Papademetriou, V.; Deedwania, P. C.; Schaefer, E. J.; McNamara, J. R.; Kashyap, M. L.; Hershman, J. M.; Wexler, L. F.; Rubins, H. B.; Braun, B. Relation of gemfibrozil treatment and lipid levels with major coronary events. VA-HIT: a randomized controlled trial. J. Am. Med. Assoc. 2001, 285, 1585-1591.
45. (b) Rubins, H. B.; Robins, S. J.; Collins, D.; Fye, C. L.; Anderson, J. W.; Elam, M. B.; Faas, F. H.; Linares, E.; Schaefer, E. J.; Schectman, G.; Wilt, T. J.; Wittes, J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N. Engl. J. Med. 1999, 341, 410-418.
46. (a) Brewer, H. B. B. Focus on high-density lipoproteins in reducing cardiovascular risk. Am. Heart J. 2004, 148, S14-S18.
47. (b) Dean, B. B.; Borenstein, J. E.; Henning, J. M.; Knight, K.; Merz, C. N. B. Can change in HDLc levels reduce cardiovascular risk? Am. Heart J. 2004, 147, 966-976.
48. (c) Rader, D. J. Effects of non-statin lipid drug therapy on high-density lipoprotein metabolism. Am. J. Cardiol. 2003, 91, 18E-23E.
49. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: The bezafibrate infarction prevention (BIP) study. Circulation 2000, 102, 21-27.
50. Capuzzi, D. M.; Guyton, J. R.; Morgan, J. M.; Goldberg, A. C.; Kreisberg, R. A.; Brusco, O. A.; Brody, J. Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. Am. J. Cardiol. 1998, 82, 74U-81U.
51. (a) Taylor, A. J.; Sullenberger, L. E.; Lee, H. J.; Lee, J. K.; Grace, K. A. Arterial biology for the investigation of the treatment effects of reducing cholesterol (ARBITER) 2: A double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004, 110, 3512-3517.
52. (b) Wolfe, M. L.; Vartanian, S. F.; Ross, J. L.; Bansavich, L.-L.; Mohler, E. R.; Meagher, E.; Friedrich, C. A.; Rader, D. J. Safety and effectiveness of Niaspan when added sequentially to a statin for treatment of dyslipidemia. Am. J. Cardiol. 2001, 87, 476-479.
53. Canner, P. L.; Berge, K. G.; Wenger, N. K.; Stamler, J.; Friedman, L.; Prineas, R. J.; Friedewald, W. Fifteen year mortality in coronary drug project patients: long-term benefit with niacin. J. Am. Coll. Cardiol. 1986, 8, 1245-1255.
54. (a) Tall, A. R.; Wang, N.; Mucksavage, P. Is it time to modify the reverse cholesterol transport model? J. Clin. Invest. 2001, 108, 1273-1275.
55. (b) Bruce, C.; Chouinard, R. A., Jr.; Tall, A. R. Plasma lipid transfer proteins, high-density lipoproteins, and reverse cholesterol transport. Annu. Rev. Nutr. 1998, 18, 297-330.
56. (c) Pieters, M. N.; Schouten, D.; Berkel, T. J. C. Van. In vitro and in vivo evidence for the role of HDL in reverse cholesterol transport. Biochim. Biophys. Acta 1994, 1225, 125-134.
57. (a) Navab, M.; Hama, S. Y.; Anantharamaiah, G. M.; Hassan, K.; Hough, G. P.; Watson, A. D.; Reddy, S. T.; Sevanian, A.; Fonarow, G. C.; Fogelman, A. M. Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein. J. Lipid Res. 2000, 41, 1481-1508.
58. (b) Suc, I.; Escargueil-Blanc, I.; Troly, M.; Salvayre, R.; Negre-Salvayre, A. HDL and apoA prevent cell death of endothelial cells induced by oxidized LDL. Arterioscler., Thromb., Vasc. Biol. 1997, 17, 2158-2166.
59. Ansell, B. J.; Navab, M.; Hama, S.; Kamranpour, N.; Fonarow, G.; Hough, G.; Rahmani, S.; Mottahedeh, R.; Dave, R.; Reddy, S. T.; Fogelman, A. M. Inflammatory/anti-inflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 2003, 108, 2751-2756.
60. Schaefer, E. J.; Heaton, W. H.; Wetzel, M. G.; Brewer, H. B. Plasma apolipoprotein A-1 absence associated with a marked reduction of high-density lipoproteins and premature coronary artery disease. Arteriosclerosis 1982, 2, 16-26.
61. Boekholdt, S. M.; Kuivenhoven, J.-A.; Wareham, N. J.; Peters, R. J. G.; Jukema, J. W.; Luben, R.; Bingham, S. A.; Day, N. E.; Kastelein, J. J. P.; Khaw, K.-T. Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women. Circulation 2004, 110, 1418-1423.
62. de Grooth, J. G.; Smilde, T. J.; van Wissen, S.; Klerkx, A. H. E. M.; Zwinderman, A. H.; Fruchart, J.-C.; Kastelein, J. J. P.; Stalenhoef, A. F. H.; Kuivenhoven, J. A. The relationship between cholesteryl ester transfer protein levels and risk factor profile in patients with familial hypercholesterolemia. Atherosclerosis 2004, 173, 261-267 .
63. Koizumi, J.; Inazu, A.; Yagi, K.; Koizumi, I.; Uno, Y.; Kajinami, K.; Miyamoto, S.; Moulin, P.; Tall, A. R.; Mabuchi, H. Serum lipoprotein lipid concentration and composition in homozygous and heterozygous patients with cholesteryl ester transfer protein deficiency. Atherosclerosis 1991, 90, 189-196.
64. Inazu, A.; Jiang, X.-C.; Haraki, T.; Yagi, K.; Kamon, N.; Koizumi, J.; Mabichi, H.; Takeda, R.; Takata, K. Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high-density lipoprotein. J. Clin. Invest. 1994, 94, 1872-1882.
65. Burchfiel, C. M.; Abbott, R. D.; Sharp, D. S.; Curb, J. D.; Rodriguez, B. L.; Yano, K. Distribution and correlates of lipids and lipoproteins in elderly Japanese-American men. The Honolulu heart program. Arterioscler., Thromb., Vasc. Biol. 1996, 16, 1356-1364.
66. Zhong, S.; Sharp, D. S.; Grove, J. S.; Bruce, C.; Yano, K.; Curb, J. D.; Tall, A. R. Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J. Clin. Invest. 1996, 97, 2917-2923.
67. Curb, J. D.; Abbott, R. D.; Rodriguez, B. L.; Masaki, K.; Chen, R.; Sharp, D. S.; Tall, A. R. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly. J. Lipid Res. 2004, 45, 948-953.
68. Nagano, M.; Yamashita, S.; Hirano, K.; Takano, M.; Maruyama, T.; Ishihara, M.; Sagehashi, Y.; Kujiraoka, T.; Tanaka, K.; Hattori, H.; Sakai, N.; Nakajima, N.; Egashira, T.; Matsuzawa, Y. Molecular mechanisms of cholesteryl ester transfer protein deficiency in Japanese. J. Atheroscler. Thrombosis 2004, 11, 110-121.
69. Ordovas, J. M.; Cupples, L. A.; Corella, D.; Otvos, J. D.; Osgood, D.; Martinez, A.; Lahoz, C.; Coltell, O.; Wilson, P. W. F.; Schaefer, E. J. Polymorphism with variations in lipoprotein subclasses and coronary heart disease risk. The Framingham Study. Arterioscler., Thromb., Vasc. Biol. 2000, 20, 1323-1329.
70. Brousseau, M. E.; O'Connor, J. J.; Ordovas, J. M.; Collins, D.; Otvos, J. D.; Massov, T.; McNamara, J. R.; Rubins, H. B.; Robins, S. J.; Schaefer. E. J. Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency. Veterans affairs HDL cholesterol intervention trial. Arterioscler., Thromb., Vasc. Biol. 2002, 22, 1148-1154.
71. Liu, S.; Schmitz, C.; Stampfer, M. J.; Sacks, F.; Hennekens, C. H.; Lindpaintner, K.; Ridker, P. M. A prospective study of TaqIB polymorphism in the gene coding for cholesteryl ester transfer protein and risk of myocardial infarction in middle-aged men. Atherosclerosis 2002, 161, 469-474.
72. Bruce, C.; Sharp, D. S.; Tall, A. R. Relationship of HDL and coronary heart desease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hyperalphalipoproteinemia. J Lipid Res. 1998, 39, 1071-1078.
73. Agerholm-Larsen, B.; Tybjaerg-Hansen, A.; Schnohr, P.; Steffensen, R.; Nordestgaard, B. G. Common cholesteryl transfer protein mutations, decreased HDL cholesterol, and possible decreased risk of ischemic heart disease. The Copenhagen city heart study. Circulation 2000, 102, 2197-2203.
74. (a) Atzmon, G.; Rincon, M.; Rabizadeh, P.; Barzilai, N. Biological evidence for inheritance of exceptional longevity. Mech. Ageing Dev. 2005, 126, 341-345.
75. (b) Barzilai, N.; Atzmon, G.; Schechter, C.; Schaefer, E. J.; Cupples, A. L.; Lipton, R.; Cheng, S.; Shuldiner, A. R. Unique lipoprotein phenotype and genotype associated with exceptional longevity. J. Am. Med. Assoc. 2003, 290, 2030-2040.
76. (a) Arai, Y.; Hirose, N.; Yamamura, K.; Nakazawa, S.; Shimizu, K. Takayama, M.; Ebihara, Y.; Homma, S.; Gondo, Y.; Masui, Y.; Inagaki, H. Deficiency of cholesteryl ester transfer protein and gene polymorphisms of lipoprotein lipases and hepatic lipase are not associated with longevity. J. Mol. Med. 2003, 81, 102-109.
77. (b) Arai, Y.; Hirose, N. Aging and HDL metabolism in elderly people more than 100 years old. J. Atheroscler. Thromb. 2004, 11, 246-252 .
78. (a) Yamashita, S.; Maruyama, T.; Hirano, K.-I.; Sakai, N.; Nakajima, N.; Matsuzawa, Y. Impairment of reverse cholesterol transport system and atherosclerosis. In Lipoprotein Metabolism and Atherogenisis; Kita, T.; Yokode, M., Eds.; Springer-Verlag: Tokyo, Japan, 2000; pp 115-123.
79. (b) Hill, S. A.; Mcqueen, M. J. Reverse cholesterol transport: a review of the process and its clinical implications. Clin. Biochem. 1997, 30, 517-525.
80. (c) Krause, B. R.; Auerbach, B. J. Reverse cholesterol transport and future pharmacological approaches to the treatment of atherosclerosis. Curr. Opin. Invest. Drugs 2001, 2, 375-381.
81. Ishigami, M.; Yamashita, S.; Sakai, N.; Hirano, K.-I.; Arai, T.; Maruyama, T.; Takami, S.; Koyama, M.; Kameda-Takemura, K.; Matsuzawa, Y. High-density lipoproteins from probucol-treated patients have increased capacity to promote cholesterol efflux from mouse peritoneal macrophages loaded with acetylated low-density lipoproteins. Eur. J. Clin. Invest. 1997, 27, 285-292.
82. Ishigami, M.; Yamashita, S.; Sakai, N.; Arai, T.; Hirano, K.; Hiraoka, H.; Kameda-Takemura, K.; Matsuzawa, Y. Large and cholesteryl ester-rich high-density lipoproteins in cholesteryl ester transfer protein (CETP) deficiency cannot protect macrophages from cholesterol accumulation induced by acetylated low-density lipoproteins. J. Biochem. 1994, 33, 257-262.
83. Zhang, Z.; Yamashita, S.; Hirano, K.; Nakagawa-Toyama, Y.; Matsuyama, A.; Nishida, M.; Sakai, N.; Fukasawa, M.; Arai, H.; Miyagawa, J.; Matsuzawa, Y. Expression of cholesteryl ester transfer protein in human atherosclerotic lesions and its implication in reverse cholesterol transport. Atherosclerosis 2001, 159, 67-75.
84. Collet, X.; Tall, A. R.; Serajuddin, H.; Guendouzi, K.; Royer, L.; Oliveira, H.; Barbaras, R.; Jiang, X.; Francone, O. L. Remodeling of HDL by CETP in vivo and by CETP and hepatic lipase in vitro results in enhanced uptake of HDL CE by cells expressing scavenger receptor B-I. J. Lipid Res. 1999, 40, 1185-1193.
85. Stein, O.; Dabach, Y.; Hollander, G.; Ben-Nairn, M.; Halperin, G.; Stein, Y. Reverse cholesterol transport in mice expressing simian cholesteryl ester transfer protein. Atherosclerosis 2002, 164, 73-78.
86. Ha, Y. C.; Barter, P. J. Differences in plasma cholesteryl ester transfer protein in sixteen vertebrate species. Comp. Biochem. Physiol. B 1985, 71, 265-269.
87. Agellon, L. B.; Walsh, A.; Hayek, T.; Moulin, P.; Jiang, X. C.; Shelanski, S. A.; Breslow, J. L.; Tall, A. R. Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice. J. Biol. Chem. 1991, 266, 10796-10801.
88. Marotti, K. R.; Castle, C. K.; Boyle, T. P.; Lin, A. H.; Murray, R. W.; Melchior, G. W. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature 1993, 364, 73-75.
89. Plump, A, S.; Masucci-Magoulas, L.; Bruce, C.; Bisgaier, C. L.; Breslow, J. L.; Tall, A. R. Increased atherosclerosis in apoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler., Thromb., Vasc. Biol. 1999, 19, 1105-1110.
90. Cazita, P. M.; Berti, J. A.; Aoki, C.; Gidlund, M.; Harada, L. M.; Nunes, V. S.; Quintao, E. C. R.; Oliveira, H. C. F. Cholesteryl ester transfer protein expression attenuates atherosclerosis in ovariectomized mice. J. Lipid Res. 2003, 44, 33-40.
91. Evans, G. F.; Bensch, W. R.; Apelgren, L. D.; Bailey, D.; Kauffman, R. F.; Bumol, T. F.; Zuckerman, S. H. Inhibition of cholesteryl ester transfer protein in normocholesterolemic and hypercholesterolemic hamsters: Effects on HDL subspecies, quantity, and apolipoprotein distribution. J. Lipid Res. 1994, 35, 1634-1645.
92. Sugano, M.; Makino, N.; Sawada, S.; Otsuka, S.; Watanabe, M.; Okamoto, H.; Kamada, M.; Mizushima, A. Effect of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits. J. Biol. Chem. 1998, 273, 5033-5036.
93. Rittershaus, C. W.; Miller, D. P.; Thomas, L. J.; Picard, M. D.; Honan, C. M.; Emmett, C. D.; Pettey, C. L.; Adari, H.; Hammond, R. A.; Beattie, D. T.; Callow, A. D.; Marsh, H. C; Ryan, U. S. Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis. Arterioscler., Thromb., Vasc. Biol. 2000, 20, 2106-2112.
94. (a) Marcel, Y. L.; McPherson, R.; Hogue, M.; Czarnecka, H.; Zawadzki, Z.; Weech, P. K.; Whitlock, M. E.; Tall, A. R.; Milne, R. W. Distribution and concentration of cholesteryl ester transfer protein in plasma of normolipemic subjects. J. Clin. Invest. 1990, 85, 10-117.
95. (b) McPherson, R.; Mann, C. J.; Tall, A. R.; Hogue, M.; Martin, L.; Milne, R. W.; Marcel, Y. L. Plasma concentration of cholesteryl ester transfer protein in hyperlipoproteinemia. Arterioscler. Thromb. 1991, 11, 797-804.
96. Connolly, D. T.; McIntyre, J.; Heuvelman, D.; Remsen, E. E.; McKinnie, R. E.; Vu, L.; Melton, M.; Monsell, R.; Krul, E. S.; Glenn, K. Physical and kinetic characterization of recombinant human cholesteryl ester transfer protein. Biochem. J. 1996, 320, 39-47.
97. Nishida, H. I.; Aral H.; Nishida, T. Cholesterol ester transfer mediated by lipid transfer protein as influenced by changes in the charge characteristics of plasma lipoproteins. J. Biol. Chem. 1993, 268, 16352-16360.
98. Hesler, C. B.; Swenson, T. L.; Tall, A. R. Purification and characterization of a human plasma cholesteryl ester transfer protein. J. Biol. Chem. 1987, 262, 2275-2282.
99. Bruce, C.; Beamer, L. J.; Tall, A. R. The implications of the structure of the bactericidal/permeability-increasing protein on the lipid-transfer function of the cholesteryl ester transfer protein. Curr. Opin. Struct. Biol. 1998, 8, 426-434.
100. Craven, B. M.; DeTitta, G. T. Cholesteryl myristate. Structures of the crystalline solid and mesophases. J. Chem. Soc., Perkin Trans. 2 1976, 814-822.
101. (a) Connolly, D. T.; Krul, E. S.; Heuvelman, D.; Glenn, K. C. Inhibition of cholesteryl ester transfer protein by apolipoproteins, lipopolysaccharides, and cholesteryl sulfate. Biochim. Biophys. Acta 1996, 1304, 145-160.
102. (b) Main, L. A.; Okumura-Noji, K.; Ohnishi, T.; Yokoyama, S. Cholesteryl ester transfer protein reaction between plasma lipoproteins. J. Biochem. (Tokyo) 1998, 124, 237-243.
103. (c) Kothari, H. V.; Poirier, K. J.; Lee, W. H.; Satoh, Y. Inhibition of cholesterol ester transfer protein CGS 25159 and changes in lipoproteins in hamsters. Atherosclerosis 1997, 128, 59-66.
104. Connolly, D. T.; Witherbee, B. J.; Melton, M. A.; Durley, R. C.; Grapperhaus, M. L.; McKinnis, B. R.; Vernier, W. F.; Babler, M. A.; Shieh, J.-J.; Smith, M. E.; Sikorski, J. A. Stereospecific inhibition of CETP activity by chiral N,N-disubstituted trifluoro-3-amino-2-propanols. Biochemistry 2000, 39, 13870-13879.
105. (a) Connolly, D. T.; Heuvelman, D.; Glenn, K. C. Inactivation of cholesteryl ester transfer protein by cysteine modification. Biochem. Biophys. Res. Commun. 1996, 223, 42-47.
106. (b) Epps, D. E.; Vosters, A. F. The essential role of a free sulfhydryl group in blocking the cholesteryl site of cholesteryl ester transfer protein (CETP). Chem. Phys. Lipids 2002, 114, 113-122.
107. Hope, H. R.; Heuvelman, D.; Duffin, K.; Smith, C.; Zablocki, J.; Schilling, R.; Hegde, S.; Lee, L.; Witherbee, B.; Baganoff, M.; Bruce, C.; Tall, A. R.; Krul, E.; Glenn, K.; Connolly, D. T. Inhibition of cholesteryl ester transfer protein by substituted dithiobis-nicotinic acid dimethyl ester: involvement of a critical cysteine. J. Lipid Res. 2000, 41, 1604-1610.
108. Shinkai, H.; Maeda, K.; Yamasaki, T.; Okamoto, H.; Uchida, I. Bis-[2-(acylamino)-phenyl] disulfides, 2-(acylamino)benzenethiols, and S-[2-(acylamino)phenyl] alkane-thioates as novel inhibitors of cholesteryl ester transfer protein. J. Med. Chem. 2000, 43, 3566-3572.
109. Okamoto, H.; Yonemori, F.; Wakitani, K.; Minowa, T.; Maeda, K.; Shinkai, H. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature 2000, 406, 203-207.
110. (a) Alegret, M.; Silvestre, J. S.; Castaner, J. JTT-705: treatment of lipoprotein disorders cholesteryl ester transfer protein inhibitor. Drugs Future 2004, 29, 787-792.
111. (b) Linders, J. T. M. JTT-705 (Japan Tobacco). Curr. Opin. Invest. Drugs 2004, 5, 339-343.
112. Shinkai, H.; Maeda, K.; Yamasaki, T.; Okamoto, H. CETP activity inhibitors. U.S. Patent 6,426,365, July 30, 2002.
113. (b) Shinkai, H.; Maeda, K.; Yamasaki, T.; Okamoto, H. CETP activity inhibitors. U.S. Patent 6,753,346, June 22, 2004.
114. Maeda, K.; Okamoto, H.; Shinkai, H. S-[2-(Acylamino)phenyl] 2,2-dimethylpropane-thioates as CETP Inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 2589-2591.
115. Paulsen, H.; Schmeck, C.; Brandes, A.; Schmidt, G.; Stoltetuss, J.; Wirtz, S. N.; Loegers, M.; Naab, P.; Bremm, K.-D.; Bischoff, H.; Schmidt, D.; Zaiss, S.; Antons, S. Fluorine-substitution in cholesteryl ester transfer protein inhibitors (CETP-inhibitors): biology, chemistry, SAR, and properties. Chimia 2004, 58, 123-127.
116. (a) Schmidt, G.; Angerbauer, R.; Brandes, A.; Logers, M.; Muller-Gliemann, M.; Bischoff, H.; Schmidt, D.; Wohlfeil, S. 2-Aryl-substituted pyridines. U.S. Patent 5,925,645, July 20, 1999.
117. (b) Schmidt, G.; Angerbauer, R.; Brandes, A.; Logers, M.; Muller-Gliemann, M.; Bischoff, H.; Schmidt, D.; Wohlfeil, S. 2-Aryl-substituted pyridines. U.S. Patent 6,127,383, October 3, 2000.
118. Mueller-Gliemann, M.; Angerbauer, R.; Brandes, A.; Loegers, M.; Schmeck, C.; Schmidt, G.; Bremm, K.-D.; Bischoff, H.; Schmidt, D. 5-Hydroxyalkyl substituted phenyls and their use in medicaments for the treatment of atherosclerosis and hyperlipidemia. U.S. Patent 6,121,330, September 19, 2000.
119. Mueller-Gliemann, M.; Angerbauer, R.; Brandes, A.; Loegers, M.; Schmeck, C.; Schmidt, G.; Bremm, K.-D.; Bischoff, H.; Schmidt, D. Preparation of 2-alkyl-3-benzyl-5-hydroxy-4-phenylquinolines and related compounds as antiarteriosclerotics. Patent Application WO9839299, September II, 1998.
120. Schmeck, C.; Mueller-Gliemann, M.; Schmidt, G.; Brandes, A.; Angerbauer, R.; Loegers, M.; Bremm, K.-D.; Bischoff, H.; Schmidt, D.; Schuhmacher, J. Heterocyclic-fused pyridines. U.S. Patent 5,932,587, August 3, 1999.
121. Schmidt, G.; Brandes, A.; Angerbauer, R.; Logers, M.; Muller-Gliemann, M.; Schmeck, C.; Bremm, K.-D.; Bischoff, H.; Schmidt, D.; Schuhmacher, J.; Giera, H.; Paulsen, H.; Naab, P.; Conrad, M.; Stoltefuss, J. Preparation of tetrahydroquinolines and analogs as cholesteryl ester transfer protein inhibitors. U.S. Patent 6,207,671, March 27, 2001.
122. (b) Schmidt, G.; Stoltetuss, J.; Loegers, M.; Brandes, A.; Schmeck, C.; Bremm, K.-D.; Bischoff, H.; Schmidt, D. 4-Phenyltetrahydroquinolines utilised as inhibitors of cholesterol ester transfer protein. U.S. Patent 6,562,976, May 13, 2003.
123. Schmidt, G.; Stoltefuss, J.; Loegers, M.; Brandes, A.; Schmeck, C.; Bremm, K.-D.; Bischoff, H.; Schmidt, D. Tetrahydroquinolines, processes for their preparation, pharmaceutical compositions containing them, and their use to prevent or treat hyperlipoproteinaemia. U.S. Patent 6.291,477, September 18, 2001.
124. Gielen, H.; Goldmann, S.; Keldenich, J.; Paulsen, H.; Schmeck, C.; Siegel, S.; Bischoff, H.; Raabe, M.; Schmidt, D.; Faeste, C. Preparation of spirocyclobutyltetrahydroquinolinols as cholesteryl ester transfer protein (CETP) inhibitors. Patent Application WO2003/028727, April 10, 2003.
125. (a) Brandes, A.; Logers, M.; Stoltefuss, J.; Schmidt, G.; Bremm, K.-D.; Bischoff, H.; Schmidt, D.; Antons, S.; Paulsen, H.; Muller, S. N.; Naab, P.; Schmeck, C. Substituted tetrahydronaphthaline and analogous compounds. U.S. Patent 6,586,613, July 1, 2003.
126. (b) Paulsen, H.; Antons, S.; Brandes, A.; Logers, M.; Muller, S. N.; Naab, P.; Schmeck, C.; Schneider, S.; Stoltefuss, J. Stereoselective Mukaiyama-Michael/Michael/aldol domino cyclization as the key step in the synthesis of pentasubstituted arenes: an efficient access to highly active inhibitors of cholesteryl ester transfer protein (CETP). Angew. Chem., Int. Ed. 1999, 38, 3373-3375.
127. Ruggeri, R. B.; Wester, R. T.; Magnus-Aryitey, G. Discovery of CP-529,414: A potent synthetic inhibitor of human plasma cholesteryl ester transfer protein (CETP). Abstracts of Papers, 225th National Meeting of the American Chemical Society, New Orleans, LA, March 23-27, 2003; American Chemical Society: Washington, DC, 2003; MEDI-156.
128. (a) Goldstein, S. W.; Makowski, M. R.; Ruggeri, R. B.; Wester, R. T. Oxy-substituted 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines. U.S. Patent 6,362,198, March 26, 2002.
129. (b) Goldstein, S. W.; Makowski, M. R.; Ruggeri, R. B.; Wester, R. T. Oxy-substituted 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines. U.S. Patent 6,140,342, October 31, 2000.
130. (a) DeNinno, M. P.; Magnus-Aryitey, G. T.; Ruggeri, R. B.; Wester, R. T. 4-Carboxy-amino-2-substituted-1,2,3,4-tetrahydroquinolines as CETP inhibitors. Patent Application WO2000/17164, March 30. 2000.
131. (b) DeNinno, M. P.; Mularski, C. J.; Ruggeri, R. B.; Wester R. T. 4-Carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines. U.S. Patent 6,395,751, May 28, 2002.
132. (c) DeNinno, M. P.; Magnus-Aryitey, G. T.; Ruggeri, R. B.; Wester, R. T. 4-Amino-substituted-2-substituted-1,2,3,4-tetrahydroquinolines. U.S. Patent 6,489,478. December 3, 2002.
133. (d) DeNinno, M. P.; Magnus-Aryitey, G. T.; Ruggeri, R. B.; Wester, R. T. 4-Carboxy-amino-2-substituted-1,2,3,4-tetrahydroquinolines. U.S. Patent 6,586,448, July 1, 2003.
134. Lloyd, D. B.; Lira, M. E.; Wood, L. S.; Durham, L. K.; Freeman, T. B.; Preston, G.; Qiu, X.; Sugarman, E.; Bonnette, P.; Lanzetti, A.; Milos, P. M.; Thompson, J. F. Cholesteryl ester transfer protein variants have differential stability but uniform inhibition by torcetrapib. J. Biol. Chem. 2005, 280, 14918-14922.
135. Chang, G.; Didiuk, M. T.; Finneman, J. I.; Garigipati, R. S.; Kelley, R. M.; Perry, D. A.; Ruggeri, R. B.; Bechle, B. M. 1,2,4-Substituted 1,2,3,4-tetrahydro- and 1,2-dihydro-quinoline and 1,2,3,4-tetrahydroquinoxaline derivatives as CETP inhibitors for the treatment of atherosclerosis and obesity. Patent Application WO2004/085401, October 7, 2004.
136. (a) Pfizer press release, November 20, 2003.
137. (b) Pfizer 2003 and 2004 annual reports.
138. (a) Allen, D. J. M.; Appleton, T. A.; Brostrom, L. R.; Tickner, D. L. Preparation of (2R,4S)-4-[(3,5-bistrifluoromethylbenzyl)methoxycarbonylamino]-2- ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as CETP inhibitor. Patent Application WO01040190, June 7, 2001.
139. (b) Damon, D. B.; Dugger. R. W.; Scott, R. W. Methods for preparing CETP inhibitors. Patent Application WO2002/088085, November 7, 2002.
140. (c) Damon, D. B.; Dugger, R. W.; Scott, R. W. Methods for preparing 4-amino-1,2,3,4-tetra-hydroquinoline-2-carboxylates. Patent Application WO2002/088069, November 7, 2002.
141. (d) Damon, D. B.; Dugger, R. W.; Scott, R. W. Intermediates of CETP inhibitors. U.S. Patent 6,689,897, February 10, 2004.
142. (e) Damon, D. B.; Dugger, R. W.; Scott, R. W. Intermediates of CETP inhibitors. U.S. Patent 6,706,881, March 16, 2004.
143. (f) McIntyre, J. A.; Castaner, J. Torcetrapib. Drugs Future 2005, 30, 344-349.
144. Tanaka, T.; Sugawara, M.; Maeda, H.; Nishiyama, A.; Yasohara, Y.; Nagashima, N. Processes for production of (R)-3-[4-(trifluoromethyl)- phenylamino]pentanamide derivatives. Patent Application WO2004/083166, September 30, 2004.
145. (a) Kelley, R. M.; McCarthy, K. E.; Miller, S. A.; Nesler, M. J.; Schildknegt, K.; Wager, C. B.; Zandi, K. S. The Synthesis of Isotopically Labelled CETP Inhibitors. In Synthesis and Applications of Isotopically Labelled Compounds, Proceedings of the 8th International Symposium, Boston, MA, June 1-5, 2003; Dean, D. C., Filer, C. N., McCarthy, K. E., Eds.; John Wiley & Sons Ltd.; Chichester, U.K., 2004.
146. (b) Dalvie, D. K.; Ruggeri, R. B. CETP inhibitors and metabolites thereof. Patent Application WO2005/033082, April 14, 2005.
147. (a) Ross, P. R. Preparation of anhydrous CETP inhibitor. U.S. Patent Application 2003/0065010, April 3. 2003.
148. (b) Allen, D. J. M.; Appleton, T. A.; Brostrom, L. R.; Tickner, D. L. 4-Carboxy-amino-2-ethyl-1,2,3,4-tetrahydroquinoline crystal as CETP inhibitor. Patent Application WO2001/040190, June 7, 2001.
149. (a) Curatolo, W. J.; Friesen, D. T.; Gumkowski, M. J.; Lorenz, D. A.; Nightingale, J. A. S.; Ruggeri, R. B.; Shanker, R. M. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors. Patent Application WO2002/011710, February 14, 2002.
150. (b) Babcock, W. C.; Crew, M. D.; Friesen, D. T.; Rabenstein, M. D.; Smithey, D. T.; Shanker, R. M. Pharmaceutical compositions containing polymer and drug assemblies. Patent Application WO2003/000226, January 3, 2003.
151. (c) Babcock, W. C.; Friesen, D. T.; Shanker, R. M.; Smithey, D. T.; Tadday, R. Pharmaceutical compositions of adsorbates of amorphous drug. Patent Application WO2003/000238, January 3, 2003.
152. (d) Crew, M. D.; Friesen, D. T.; Keiner, R. J.; Shanker, R. M.; West, J. B. Pharmaceutical compositions comprising low-solubility and/or acid-sensitive drugs and neutralized acidic polymers. Patent Application WO2003/000292, January 3, 2003.
153. (e) Babcock, W. C.; Curatolo, W. J.; Friesen, D. T.; Ketner, R. J.; Lo, J. B.; Nightingale, J. A. S.; Shanker, R. M.; West, J. B. Pharmaceutical compositions containing a solid dispersion of a poorly-soluble drug in a matrix and a solubility-enhancing polymer. Patent Application WO2003/000294, January 3, 2003.
154. (f) Gumkowski, M. J.; Murdande, S. B.; Perlman, M. E.; Lombardo, F. Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors and surfactants. Patent Application WO2003/000295, January 3, 2003.
155. (g) Beyerinck, R. A.; Ray, R. J.; Dobry, D. E.; Settell, D. M. Method for making homogeneous spray-dried solid amorphous drug dispersions using pressure nozzles. Patent Application WO2003/063821, August 7, 2003.
156. (h) Beyerinck, R. A.; Ray, R. J.; Dobry, D. E.; Settell, D. M.; Spence, K. R.; Deibele, H. L. M. Method for making homogeneous spray-dried solid amorphous drug dispersions utilizing modified spray-drying apparatus. Patent Application WO2003/063822, August 7, 2003.
157. (i) Hancock, B. C.; Schadtle, S. J.; Appel, L, E.; Byers, J, E.; Crew, M. D.; Friesen, D. T. Immediate-release dosage forms containing solid drug dispersions. Patent Application WO2003/063831, August 7, 2003.
158. (j) Curatolo, W. J.; Gumkowski, M. J.; Ruggeri, R. B.; Shanker, R. M.; Crew, M. D.; Friesen, D. T.; Lorenz, D. A.; Nightingale, J. A. S. Pharmaceutical compositions comprising a solid amorphous dispersion of cholesteryl ester transfer protein inhibitors. Patent Application WO2003/063832, August 7, 2003.
159. (k) Perlman, M. E.; Shanker, R. M.; Babcock, W. C.; Friesen, D, T.; Rabenstein, M. D.; Smithey, D. T. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic micro-phase-forming materials. Patent Application WO2003/063833, August 7, 2003.
160. (l) Curatolo, W. J.; Sutton, S. C.; Appel, L. E. Controlled release dosage forms containing cholesteryl ester transfer protein inhibitor. Patent Application WO2003/063868, August 7, 2003.
161. (m) Crew, M. D.; Curatolo, W. J.; Friesen, D. T.; Gumkowski, M. J.; Lorenz, D. A.; Nightingale, J. A. S.; Ruggeri, R. B.; Shanker, R. M. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors. U.S. Patent Application 2003/186952, October 2, 2003.
162. (n) Beyerinck, R. A.; Dobry, D. E.; Friesen, D. T.; Setteil, D. M.; Ray, R. J. Spray drying processes for forming solid amorphous dispersions of drugs and polymers. Patent Application WO2005/011636, February 10, 2005.
163. Rheinhard, E. J.; Wang, J. L.; Durley, R. C.; Fobian, Y. M.; Grapperhaus, M. L.; Hickory, B. S.; Massa, M. A.; Norton, M. B.; Promo, M. A.; Tollefson, M. B.; Vernier, W. F.; Connolly, D. T.; Witherbee, B. J.; Melton, M. A.; Regina, K. J.; Smith, M. E.; Sikorski, J. A. Discovery of a simple picomolar inhibitor of cholesteryl ester transfer protein. J. Med. Chem. 2003, 46, 2152-2168.
164. (a) Durley, R. C.; Grapperhaus, M. L.; Massa, M. A.; Mischke, D. A.; Parnas, B. L.; Fobian, Y. M.; Rath, N. P.; Honda, D. D.; Zeng, M.; Connolly, D. T.; Heuvelman, D. M.; Witherbee, B. J.; Glenn, K. C.; Krul, E. S.; Smith, M. E.; Sikorski, J. A. Discovery of chiral N,N-disubstiuted trifluoro-3-amino-2- propanols as potent inhibitors of cholesteryl ester transfer protein. J. Med. Chem. 2000, 43, 4575-4578.
165. (b) Durley, R. C.; Grapperhaus, M. L.; Hickory, B. S.; Massa, M. A.; Wang, J. L.; Spangler, D. P.; Mischke, D. A.; Parnas, B. L.; Fobian, Y. M.; Rath, N. P.; Honda, D. D.; Zeng, M.; Connolly, D. T.; Heuvelman, D. M.; Witherbee, B. J.; Glenn, K. C.; Krul, E. S.; Smith, M. E.; Sikorski, J. A. Chiral N,N-disubstiuted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein. J. Med. Chem. 2002, 45, 3891-3904.
166. Massa, M. A.; Spangler, D. P.; Durley, R. C.; Hickory, B. S.; Connolly, D. T.; Witherbee, B. J.; Smith, M. E.; Sikorski, J. A. Novel heteroaryl replacements of aromatic 3-tetrafluoroethoxy substituents in trifluoro-3-(tertiaryamino)-2-propanols as potent inhibitors of cholesteryl ester transfer protein. Bioorg. Med. Chem. Lett. 2001, 11, 1625-1628.
167. Sikorski, J. A.; Durley, R. C.; Grapperhaus, M. L.; Massa, M. A.; Reinhard, E. J.; Fobian, Y. M.; Tollefson, M. B.; Wang, L.; Hickory, B. S.; Norton, M. B.; Vernier, W. F.; Mischke, D. A.; Promo, M. A.; Hamme, A. T.; Spangler, D. P.; Rueppel, M. L. Preparation of halogenated substituted (R)-N-benzyl-N-phenyl-aminoalcohols with cholesteryl ester transfer protein inhibiting activity for therapeutic use in the treatment of atherosclerosis and other coronary artery diseases. U.S. Patent Application 2002/177708, November 28, 2002.
168. Ramachandran, P. V.; Gong, B.; Brown, H. C. Chiral synthesis via organoboranes. 40. Selective reductions. 55. A simple one-pot synthesis of the enantiomers of trifluoromethyloxirane. A general synthesis in high optical purities of α-trifluoromethyl secondary alcohols via the ring-cleavage reactions of the epoxide. J. Org. Chem. 1995, 60, 41-46.
169. Sikorski, J. A.; Durley, R. C.; Mischke, D. A.; Reinhard, E. J.; Fobian, Y. M.; Tollefson, M. B.; Wang, L.; Grapperhaus, M. L.; Hickory, B. S.; Massa, M. A.; Norton, M. B.; Vernier, W. F.; Parnas, B. L.; Promo, M. A.; Hamme, A. T.; Spangler, D. P.; Rueppel, M. L. Substituted N-phenyl N-benzyl-aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity. U.S. Patent 6,723,753, April 20, 2004.
170. Sikorski, J. A.; Durley, R. C.; Mischke, D. A.; Reinhard, E. J.; Fobian, Y. M.; Tollefson, M. B.; Wang, L.; Grapperhaus, M. L.; Hickory, B. S.; Massa, M. A.; Norton, M. B.; Vernier, W. F.; Parnas, B. L.; Promo, M. A.; Hamme, A. T.; Spangler, D. P.; Rueppel, M. L. (R)-Chiral halogenated substituted N-benzyl-N-phenyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity. U.S. Patent 6,723,752, April 20, 2004.
171. Maeda, K.; Nagamori, H.; Nakamura, H.; Shinkai, H.; Suzuki, Y.; Takahashi, D.; Taniguchi, T. Preparation of N-phenyl or N- heterocyclyldibenzylamine compounds as inhibitors of cholesteryl ester transfer protein (CETP) and medicinal use thereof. Patent Application WO2004/020393. March 11, 2004.
172. Kori, M.; Hamaura, K.; Fuse, H.; Yamamoto, T. Preparation of aminoethanol derivatives as cholesteryl ester transfer protein inhibitors for the treatment of hyperlipidemia. Patent Application WO2002/059077, August 1, 2002.
173. (a) Bischoff, H.; Schmeck, C.; Schmidt, D.; Vakalopoulos, A.; Wirtz, G. Novel use of dioxocin-5-on derivatives. Patent Application WO2004/039364, May 13, 2004.
174. (b) Bischoff, H.; Hafner, F.-T.; Schmeck, C.; Telser, J.; Vakalopoulos, A.; Wirtz, G.; Bauser, M. 7H-Dibenzo(b,g)-(1,5)-dioxocin-5-one-derivates and their use. German Patent Application DE10250687, May 13, 2004.
175. Hua, D. H.; Huang, X.; Chen, Y.; Battina, S. K.; Tamura, M.; Noh, S. K.; Koo, S. I.; Namatame, I.; Tomoda, H.; Perchellet, E. M.; Perchellet, J.-P. Total syntheses of (+)-chloropuupehenone and (+)-chloropuupehenol and their analogues and evaluation of their bioactivities. J. Org. Chem. 2004, 69, 6065-6078.
176. Lee, L. F.; Glenn, K. C.; Connolly, D. T.; Corley, D. G.; Flynn, D. L.; Hamme, A.; Hegde, S. G.; Melton, M. A.; Schilling, R. J.; Sikorski, J. A.; Wall, N. N.; Zablocki, J. A. Substituted pyridines useful for inhibiting cholesteryl ester transfer protein activity. U.S. Patent 6,605,624, August 12, 2003.
177. (a) Alegret, M.; Silvestre, J. S.; Castaner, J. JTT-705: treatment of lipoprotein disorders cholesteryl ester transfer protein inhibitor. Drugs Future 2004, 29, 787-792.
178. (b) Linders, J. T. M. JTT-705 (Japan Tobacco). Curr. Opin. Invest. Drugs 2004, 5, 339-343.
179. (c) Okamoto, H. Development of CETP inhibitors. Lipid 2002, 13, 76-81.
180. Okamoto, H.; Iwamoto, Y.; Maki, M.; Sotani, T.; Yonemori, F.; Wakitani, K. Effect of JTT-705 on cholesteryl ester transfer protein and plasma lipid levels in normolipidemic animals. Eur. J. Pharmacol. 2003, 466, 147-154.
181. Kobayashi, J.; Okamoto, H.; O. M.; Bujo, H.; Saito, Y. Effect of HDL, from Japanese white rabbits administered a new cholesteryl ester transfer protein inhibitor JTT-705, on cholesteryl ester accumulation induced by acetylated low density lipoprotein in J774 macrophage. Atherosclerosis 2002, 162, 131-135.
182. Huang, Z.; Inazu, A.; Nohara, A.; Higashikata, T.; Mabuchi, H. Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia. Clin. Sci. 2002, 103, 587-594.
183. Shimoji, E.; Zhang, B.; Fan, P.; Saku, K. Inhibition of cholesteryl ester transfer protein increases serum apolipoprotein (apo) A-I levels by increasing the synthesis of apo A-I in rabbits. Atherosclerosis 2004, 172, 247-257.
184. Zhang, B.; Fan, P.; Shimoji, E.; Xu, H.; Takeuchi, K.; Bian, C.; Saku, K. Inhibition of cholesteryl ester transfer protein activity by JTT-705 increases apolipoprotein E-containing high-density lipoprotein and favorably affects the function and enzyme composition of high-density lipoprotein in rabbits. Arterioscler., Thromb., Vasc. Biol. 2004, 24, 1910-1915.
185. Sunami, M.; Serigano, T. Pharmaceutical compositions of CETP inhibitors. Patent Application WO2004/082593, September 30, 2004.
186. Urata, Y.; Ishikawa, T. Administration of food for increasing the oral bioavailability of 5-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]-2- methylpropanethioate. Patent Application WO2004/082675, September 30, 2004.
187. Bischoff, H. Low molecular weight CETP inhibitors: A new approach for the treatment of hypoalphalipoproteinemia? Presented at the 2000 HDL Cholesterol: 1st Annual Metabolic Pathways and Drug Developments Conference, Boston, MA, April 4, 2000.
188. Morehouse, L. A.; Sugarman, E. D.; Bourassa, P.-A.; Milici, A. J. HDL elevation by the CETP-inhibitor torcetrapib prevents aortic atherosclerosis in rabbits. Abstracts from the 2004 American Heart Association Meeting, New Orleans, LA. Circulation 2004, 110 (Suppl.), III-243.
189. (a) Ruggeri, R. B. Use of cholesteryl ester transfer protein (CETP) inhibitors and anti-hypertensive agents and optional HMG-CoA reductase inhibitors for the treatment of cardiovascular conditions. Patent Application WO2004/004777, January 15, 2004.
190. (b) Nguyen, T. T.; Shear, C. L.; Revkin, J. H.; Ruggeri, R. B. Therapeutic use and pharmaceutical compositions of cholesterol ester transfer protein (CETP) inhibitors and optional HMG-CoA reductase inhibitors and/or antihypertensive agents. Patent Application WO2004/004778, January 15, 2004.
191. (c) Shear, C. L. Therapeutic combinations cholesterol ester transfer protein inhibitor and atorvastatin. Patent Application WO2002/013797, February 21, 2002.
192. (a) Babcock, W. C.; Friesen, D. T.; Smithey, D. T.; Shanker, R. M. Compositions of cholesteryl ester transfer protein inhibitors and HMG-COA reductase inhibitors. Patent Application WO2004/056395, July 8, 2004.
193. (b) Friesen, D. T.; Lorenz, D. A.; Lyon, D. K.; Hancock, B. C.; Mcdermott, T. J.; Shanker, R. M. Dosage forms comprising a CETP inhibitor and a HMG-CoA reductase inhibitor. Patent Application WO2004/056359, July 8, 2004.
194. (c) Friesen, D. T.; Lyon, D. K.; Lorenz, D. A.; Keiner, R. J.; Mcdermott, T. J.; Shanker, R. M. Dosage forms comprising a CETP inhibitor and a HMG-CoA reductase inhibitor. Patent Application WO2004/056358, July 8, 2004.
195. Curatolo, W. J.; Friesen, D. T.; Sutton, S. C. Controlled release dosage forms containing cholesteryl ester transfer protein inhibitors and immediate release of HMG-CoA reductase inhibitors. Patent Application WO2005/011634, February 10, 2005.
196. Keller, B. T.; Sikorski, J. A.; Glenn, K. C.; Connolly, D. T.; Smith, M. E.; Schuh, J. R. Combinations of ileal bile acid transport inhibitors and cholesteryl ester transfer protein inhibitors for cardiovascular indications. U.S. Patent 6,458,851, October 1, 2002.
197. Sikorski, J. A.; Glenn, K. C. Combinations of cholesteryl ester transfer protein inhibitors and fibric acid derivatives for cardiovascular indications. U.S. Patent 6,458,850, October 1, 2002.
198. Sikorski, J. A.; Glenn, K. C. Combinations of cholesteryl ester transfer protein inhibitors and bile acid sequestering agents for cardiovascular indications. U.S. Patent 6,569,905, May 27, 2003.
199. Keller, B. T.; Sikorski, J. A.; Glenn, K. C.; Connolly, D. T.; Smith, M. E.; Schuh, J. R. Combinations of cholesteryl ester transfer protein inhibitors and HMG CoA reductase inhibitors for cardiovascular indications. U.S. Patent 6,462,091, October 8, 2002.
200. Sikorski, J. A.; Glenn, K. C. Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications. U.S. Patent 6,489,366, December 3, 2002.
201. Kuivenhoven, J. A. Presentation at the 15th International Symposium on Drugs Affecting Lipid Metabolism (DALM) Congress, Venice, Italy, October 26, 2004.
202. Urata, Y.; Hoshino, S.; Kawamura, H.; Okamoto, H.; Furukawa, N. Combination comprising 5-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl] 2-methylpropane-thioate and a HMG CoA reductase inhibitor. Patent Application WO2004/098583, November 18, 2004.
203. Bayer AG. Drug Development Pipeline, Company Communication, November 30, 2000, and updated March 24, 2004.
204. Schaefer, E. J.; McNamara, J. R.; Tayler, T.; Daly, J. A.; Gleason, J. A.; Seman, L. J.; Ferrari, A.; Rubenstein, J. J. Effects of atorvastatin on fasting and postprandial lipoprotein subclasses in coronary heart disease patients versus control subjects. Am. J. Cardiol. 2002, 90, 689-696.
205. (a) Gardner, C. D.; Fortmann, S. P.; Krauss, R. M. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. J. Am. Med. Assoc. 1996, 276, 875-881.
206. (b) Lamarche, B.; St-Pierre, A. C.; Ruel, I. L.; Cantin, B.; Dagenais, G. R. Despres, J. P. A prospective, population-based study of low-density lipoprotein particle size as a risk factor for ischemic heart disease in men. Can. J. Cardiol. 2001, 17, 859-865.
207. Brousseau, M. E.; Diffenderfer, M. R.; Millar, J. S.; Nartsupha, C.; Asztalos, B. F.; Welty, F. K.; Wolfe, M. L.; Rudling, M.; Bjorkhem, I.; Angelin, B.; Mancuso, J. P.; Digenio, A. G.; Rader, D. J.; Schaefer, E. J. Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion. Arterioscler., Thromb., Vasc. Biol. 2005, 25, 1057-1064.
208. Klerkx, A. H. E. M.; de Grooth, G. J.; Zwinderman, A. H.; Jukema, J. W.; Kuivenhoven, J. A.; Kastelein, J. J. P. Cholesteryl ester transfer protein concentration is associated with progression of atherosclerosis and response to pravastatin in men with coronary artery disease (REGRESS). Eur. J. Clin. Invest. 2004, 34, 21-28.
209. Forrester, J. S.; Makkar, R.; Shah, P. K. Increasing high-density lipoprotein cholesterol in dyslipidemia by cholesteryl ester transfer protein inhibition: An update for clinicians. Circulation 2005, 111, 1847-1854.
210. Nissen, S. E.; Tuzcu, E. M.; Schoenhagen, P.; Crowe, T.; Sasiela, W. J.; Tsai, J.; Orazem, J.; Magorien, R. D.; O'Shaughnessy, C.; Ganz, P. Reversal of atherosclerosis with aggressive lipid lowering (REVERSAL) investigators. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N. Engl. J. Med. 2005, 352, 29-38.
211. LaMattina, J. L. Pfizer Research & Development Presentation, Pfizer Analysts Update, April 5, 2005.
212. Guerin, M.; Le Goff, W.; Lassel, T. S.; Van Tol, A.; Steiner, G.; Chapman, M. J. Proatherogenic role of elevated CE transfer from HDL to VLDL1 and dense LDL in type 2 diabetes: impact of the degree of triglyceridemia. Arterioscler., Thromb., Vasc. Biol. 2001, 21, 282-288.
213. Asayama, K.; Hayashibe, H.; Dobashi, K.; Uchida, N.; Nakane, T.; Kodera, K.; Shirahata, A. Increased serum cholesteryl ester transfer protein in obese children. Obes. Res. 2002, 10, 439-446.
214. Ebenbichler, C. F.; Laimer, M.; Kaser, S.; Ritsch, A.; Sandhofer, A.; Weiss, H.; Aigner, F.; Patsch, J. R. Relationship between cholesteryl ester transfer protein and atherogenic lipoprotein profile in morbidly obese women. Arterioscler., Thromb., Vasc. Biol. 2002, 22, 1465-1469.
215. Images were adapted using ScienceSlides from VisiScience (www.visiscience.com), www.sehha.com/metabolic/atherosclerosis, and www.tu-harburg.deBrunner/Lipoprotein.gif.