Identification of a potent and metabolically stable series of fluorinated diphenylpyridylethanamine-based cholesteryl ester transfer protein inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 22, Issue 20, 2012, Pages 6503-6508

  Miller, Michael M ^a   Liu, Yalei ^a   Jiang, Ji ^a   Johnson, James A ^a   Kamau, Muthoni ^a   Nirschl, David S ^a   Wang, Yufeng ^a   Harikrishnan, Lalgudi ^a   Taylor, David S ^a   Chen, Alice Ye A ^a   Yin, Xiaohong ^a   Seethala, Ramakrishna ^a   Peterson, Tara L ^a   Zvyaga, Tatyana ^a   Zhang, Jun ^a   Huang, Christine S ^a   Wexler, Ruth R ^a   Poss, Michael A ^a   Michael Lawrence, R ^a   Adam, Leonard P ^a   Salvati, Mark E ^a   more..

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

Atherosclerosis; CETP inhibitor; Cholesteryl ester transfer protein; Coronary heart disease; High density lipoprotein cholesterol; Low density lipoprotein cholesterol; Reverse cholesterol transport

Indexed keywords

ANACETRAPIB; BAY 194789; BENZOXAZOLE DERIVATIVE; CHOLESTEROL ESTER TRANSFER PROTEIN INHIBITOR; DALCETRAPIB; FLUORINE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PYRROLIDINE DERIVATIVE; SC 795; TORCETRAPIB; UNCLASSIFIED DRUG; UREA;

ARTICLE; ATHEROSCLEROSIS; BINDING AFFINITY; CHOLESTEROL TRANSPORT; DRUG METABOLISM; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; FLUORINATION; HUMAN; ISCHEMIC HEART DISEASE; NONHUMAN; PHARMACODYNAMICS; STRUCTURE ACTIVITY RELATION; TRANSGENIC MOUSE;

AMINES; ANIMALS; CHOLESTEROL ESTER TRANSFER PROTEINS; HALOGENATION; HUMANS; MICE; PYRIDINES; RATS; UREA;

EID: 84866731674     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2012.08.011     Document Type: Article

References (72)

1. AHA: (a) World Health Organization. Atlas of Heart Disease and Stroke; World Health Organization: Geneva, Switzerland, 2004.
2. National Center for Health Statistics. Health, United States, 2005 with Chartbook on Trends in the Health of Americans; National Center for Health Statistics: Hyattsville, MD, 2005, p 178.
3. Lloyd-Jones, D.; Adams, R.; Brown, T.M.; Carnethon, M.; Dai, S.; De Simone, G.; Ferguson, T.B.; Furie, K.; Gillespie, C.; Go, A.; Greenlund, K.; Haase, N.; Hailpern, S.; Ho, M.; Howard, V.; Kissela, B.; Kittner, S.; Lackland, D.; Lisabeth, L.; Marelli, A.; McDermott, M.; Meigs, J.; Mozaffarian, D.; Mussolino, M.; Nichol, G.; Roger, V.; Rosamond, W.; Sacco, R.; Sorlie, P.; Stafford, R.; Thom, T.; Wasserthiel-Smoller, S.; Wong, N.; Wylie-Rosett, J. Heart Disease and Stroke Statistics-2010 Update; A Report from the American Heart Association: Dallas, TX, 2008. Circulation 2010, 121, e1.
4. H.C. Bucher, L.E. Griffith, and G.H. Guyatt Arterioscler. Thromb. Vasc. Biol. 19 1999 187
5. Statins: Scandinavian Simvastatin Survival Study Group Lancet 1994, 344, 1383
6. J. Shepherd, S.M. Cobbe, I. Ford, C.G. Isles, A.R. Lorimer, P.W. MacFarlane, J.H. McKillop, and C.J. Packard N. Engl J. Med. 333 1995 1301
7. J.R. Downs, M. Clearfield, S. Weis, E. Whitney, D.R. Shapiro, P.A. Beere, A. Langendorfer, E.A. Stein, W. Kruyer, and A.M. Gotto JAMA 279 1998 1615
8. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002, 360, 7
9. P.S. Sever, B. Dahlof, N.R. Poulter, H. Wedel, G. Beevers, M. Caulfield, R. Collins, S.E. Kjeldsen, A. Kristinsson, G.T. McInnes, J. Mehlsen, M. Nieminen, E. O'Brien, and J. Ostergren Lancet 361 2003 1149
10. C.P. Cannon, E. Braunwald, C.H. McCabe, D.J. Rader, J.L. Rouleau, R. Belder, S.V. Joyal, K.A. Hill, M.A. Pfeffer, and A.M.N. Skene Engl. J. Med. 350 2004 1495
11. G.G. Rhoads, C.L. Gulbrandsen, and A.N. Kagan Engl. J. Med. 294 1976 293
12. T. Gordon, W.P. Castelli, M.C. Hjortland, W.B. Kannel, and T.R. Dawber Am. J. Med. 62 1977 707
13. W.P. Castelli, R.J. Garrison, P.W. Wilson, R.D. Abbott, S. Kalousdian, and W.B. Kannel J. Am. Med. Assoc. 256 1986 2835
14. W.B. Kannel Am. J. Cardiol. 76 1995 69c
15. J.-P. Despres, I. Lemieux, G.-R. Dagenais, B. Cantin, and B. Lamarche Atherosclerosis 153 2000 263
16. S.J. Robins, D. Collins, J.T. Wittes, V. Papademetriou, P.C. Deedwania, E.J. Schaefer, J.R. McNamara, M.L. Kashyap, J.M. Hershman, L.F. Wexler, H.B. Rubins, and B. Braun JAMA 285 2001 1585
17. V. Manninen, M.O. Elo, M.H. Frick, K. Haapa, O.P. Heinonen, P. Heinsalmi, P. Helo, J.K. Huttunen, P. Kaitaniemi, P. Koskinen, H. Maenppa, M. Malkonen, M. Manttari, S. Norola, A. Pasternack, J. Pikkarainen, M. Romo, T. Sjoblom, and E.A. Nikkila JAMA 260 1988 641
18. Fibrates: A.M. Gotto Jr. Circulation 103 2001 2213
19. Niacin: J.M. King, J.R. Crouse, J.G. Terry, T.M. Morgan, B.J. Spray, and N.E. Miller Am. J. Med. 97 1994 323
20. Adverse flushing effects of niacin can be mitigated by the use of extended release niacin (ERN) formulations: M.J. Chapman, G. Assmann, J.C. Fruchart, J. Shepherd, and C. Sirtori Curr. Med. Res. Opin. 20 2004 1253
21. M. McGovern Eur. Heart J. Suppl. 7 2005 F41
22. A. Gille, E.T. Bodor, K. Ahmed, and S. Offermanns Annu. Rev. Pharmacol. Toxicol. 48 2008 79
23. Flushing effect of niacin has also been reduced with the combination of ERN and laropiprant, see: J.F. Paolini, Y.B. Mitchel, R. Reyes, U. Kher, E. Lai, D.J. Watson, J.M. Norquist, A.G. Meehan, H.E. Bays, M. Davidson, and C.M. Ballantyne Am. J. Cardiol. 101 2008 625
24. R.S. Birjmohun, B.A. Hutten, J.J. Kastelein, and E.S. Stroes J. Am. Coll. Cardiol. 45 2005 185
25. P. Barter, J. Kastelein, A. Nunn, and R. Hobbs Atherosclerosis 168 2003 195
26. A.R. Tall J. Lipid Res. 34 1993 1255
27. P.J. Barter, H.B. Brewer, M.J. Chapman, C.H. Hennekens, D.J. Rader, and A.R. Tall Arterioscler. Thromb. Vasc. Biol. 23 2003 160
28. M.J. Chapman, W. Le Goff, M. Guerin, and A. Kontush Eur. Heart J. 31 2010 149
29. E. Vourvouhaki, and G.V. Dedoussis Expert Opin. Ther. Targets 12 2008 937
30. M. Cuchel, and D.J. Rader J. Am. Coll. Cardiol. 2007 1956 50
31. J.A. Sikorski, and D.T. Connolly Curr. Opin. Drug Discovery Dev. 4 2001 602
32. J.A. Sikorski, and K.C. Glenn Annu. Rep. Med. Chem. 35 2000 251
33. K.-I. Hirano, S. Yamashita, and Y. Matsuzawa Curr. Opin. Lipidol. 11 2000 589
34. A. Inazo, J. Koizumi, and H. Mabuchi Curr. Opin. Lipidol. 11 2000 389
35. L. Lagrost Adv. Vasc. Biol. 5 1999 217 (Plasma Lipids and Their Role in Disease)
36. Hamster study: G.F. Evans, W.R. Bensch, L.D. Apelgren, D. Bailey, R.F. Kauffman, T.F. Bumol, and S.H.J. Zuckerman Lipid Res. 35 1994 1634
37. Rabbit (antisense) study: M. Sugano, N. Makino, S. Sawada, S. Otsuka, M. Watanabe, H. Okamoto, M. Kamada, and A. Mizushima J. Biol. Chem. 273 1998 5033
38. Rabbit studies: H. Okamoto, F. Yonemori, K. Wakitani, T. Minowa, K. Maeda, and H. Shinkai Nature 406 2000 203
39. H. Shinkai, K. Maeda, T. Yamasaki, H. Okamoto, and I. Uchida J. Med. Chem. 43 2000 3566
40. Rabbit (JTT-705) study: J. Kobayashi, H. Okamoto, M. Otabe, H. Bujo, and Y. Saito Atherosclerosis 162 2002 131
41. Human study: R.W. Clark, T.A. Sutfin, R.B. Ruggeri, A.T. Willauer, E.D. Sugarman, G. Magnus-Aryitey, P.G. Cosgrove, T.M. Sand, R.T. Wester, J.A. Williams, M.E. Perlman, and M.J. Bamberger Arterioscler. Thromb. Vasc. Biol. 24 2004 490
42. P.J. Barter, M. Caulfield, M. Eriksson, S.M. Grundy, J.J.P. Kastelein, M. Komajda, J. Lopez-Sendon, L. Mosca, J.-C. Tardif, D.D. Waters, C.L. Shear, J.H. Revkin, K.A. Buhr, M.R. Fisher, A.R. Tall, and B.N. Brewer Engl. J. Med. 357 2007 2109
43. For reviews of clinical and pre-clinical CETP inhibitors, see: J.A. Hunt, and Z. Lu Curr. Top. Med. Chem. 9 2009 419
44. P.J.W.H. Kappelle, A. van Tol, B.H.R. Wolffenbuttel, and R.P.F. Dullaart Cardiovascular Therapeutics 29 2011 e89
45. P.P. Toth Curr. Cardiol. Rep. 13 2011 559
46. Bayer (BAY 194789): C. Schmeck, H. Gielen-Haertwig, A. Vakalopoulos, H. Bischoff, V. Li, G. Wirtz, and O. Weber Bioorg. Med. Chem. Lett. 20 2010 1740
47. M.-F. Boettcher, R. Heinig, C. Schmeck, C. Kohlsdorfer, M. Ludwig, A. Schaefer, S. Gelfert-Peukert, G. Wensing, and O. Weber Br. J. Clin. Pharmacol. 73 2012 210
48. Johnson & Johnson: T.A. Rano, E. Sieber-McMaster, P.D. Pelton, M. Yang, K.T. Demarest, and G.-H. Kuo Bioorg. Med. Chem. Lett. 19 2009 2456
49. G.-H. Kuo, T. Rano, P. Pelton, K.T. Demarest, A.C. Gibbs, W.V. Murray, B.P. Damiano, and M.A. Connelly J. Med. Chem. 52 2009 1768
50. A. Wang, C.P. Prouty, P.D. Pelton, M. Yong, K.T. Demarest, W.V. Murray, and G.-H. Kuo Bioorg. Med. Chem. Lett. 20 2010 1432
51. Late stage clinical compounds: C.J. Smith, A. Ali, M.L. Hammond, H. Li, Z. Lu, J. Napolitano, G.E. Taylor, C.F. Thompson, M.S. Anderson, Y. Chen, S.S. Eveland, Q. Guo, S.A. Hyland, D.P. Milot, C.P. Sparrow, S.D. Wright, A.-M. Cumiskey, M. Latham, L.B. Peterson, R. Rosa, J.V. Pivnichny, X. Tong, S.S. Xu, and P.J. Sinclair J. Med. Chem. 54 2011 4880 and references therein
52. C.P. Cannon, S. Shah, H.M. Dansky, M. Davidson, E.A. Brinton, A.M. Gotto, M. Stepanavage, S.X. Liu, P. Gibbons, T.B. Ashraf, J. Zafarino, Y. Mitchel, and P.N. Barter Engl. J. Med. 363 2010 2406
53. S.J. Nicholls, H.B. Brewer, J.J.P. Kastelein, K.A. Krueger, M.-D. Wang, M. Shao, B. Hu, E. McErlean, and S.E. Nissen J. Amer. Med. Assoc. 306 2011 2099
54. Z.A. Fayad, V. Mani, M. Woodward, D. Kallend, M. Abt, T. Burgess, V. Fuster, C.M. Ballantyne, E.A. Stein, J.-C. Tardif, J.H.F. Rudd, M.E. Farkouh, and A. Tawakol Lancet 378 2011 1547
55. L.S. Harikrishnan, M.G. Kamau, T.F. Herpin, G.C. Morton, Y. Liu, C.B. Cooper, M.E. Salvati, J.X. Qiao, T.C. Wang, L.P. Adam, D.S. Taylor, A.Y.A. Chen, X. Yin, R. Seethala, T.L. Peterson, D.S. Nirschl, A.V. Miller, C.A. Weigelt, K.K. Appiah, J.C. O'Connell, and R.M. Lawrence Bioorg. Med. Chem. Lett. 18 2008 2640
56. Independently the 2-arylbenzoxazole chemotype represented by 6 was also identified by researchers at Merck: C.J. Smith, A. Ali, L. Chen, M.L. Hammond, M.S. Anderson, Y. Chen, S.S. Eveland, Q. Guo, S.A. Hyland, D.P. Milot, C.P. Sparrow, S.D. Wright, and P.J. Sinclair Bioorg. Med. Chem. Lett. 20 2010 346
57. J.A. Hunt, S. Gonzalez, F. Kallashi, M.L. Hammond, J.V. Pivnichny, X. Tong, S.S. Xu, M.S. Anderson, Y. Chen, S.S. Eveland, Q. Guo, S.A. Hyland, D.P. Milot, C.P. Sparrow, S.D. Wright, and P.J. Sinclair Bioorg. Med. Chem. Lett. 20 2010 1019
58. L.S. Harikrishnan, H.J. Finlay, J.X. Qiao, M.G. Kamau, J. Jiang, T.C. Wang, J. Li, C.B. Cooper, M.A. Poss, L.P. Adam, D.S. Taylor, A.Y.A. Chen, X. Yin, P.G. Sleph, R.Z. Yang, D.F. Sitkoff, M.A. Galella, D.S. Nirschl, K. Van Kirk, A.V. Miller, C.H. Huang, M. Chang, X.-Q. Chen, M.E. Salvati, R.R. Wexler, and R.M. Lawrence J. Med. Chem. 55 2012 6162
59. Screening of the BMS compound collection was carried out using a BODIPY fluorescence assay based on: Bisgaier, C.L.; Minton, L.L.; Essenburg, A.D.; White, A.; Homan, R.J. Lipid Res. 1993, 34, 1625. After positive retests were complete, compounds were reconfirmed in a dose-response mode using a scintillation proximity assay (SPA). Potent compounds in SPA were then evaluated for activity in a human whole plasma assay (WPA).
60. 3H-CE/HDL (0.15 μl), biotinylated LDL (∼5 μg protein/ml final concentration) and unlabeled HDL (16 ug/ml final concentration) in a buffer containing 50 mM HEPES, pH 7.4, 150 mM NaCl and 0.05% sodium azide. Reactions were initiated by the addition of 10 μl of buffer containing purified human recombinant CETP, and incubated at 37 °C. At the end of the reaction, 60 μl of LEADseeker beads (#RPNQ0261, 2 mg/ml in buffer containing 1 mg/ml BSA and 0.05 mg protein/ml HDL) were added, the plates were covered and subsequently read. Background activity was determined in a set of wells that received buffer but no CETP. The level of inhibition was determined by comparing the readings in wells that contain compound to the readings in control wells containing DMSO.
61. 2:2% Dextralip 50), to precipitate LDL and VLDL. After 10 min at room temperature, 15 μl of the reaction was transferred to filter plates (Millipore, #MHVBN45) pre-wetted with 100 μl phosphate buffered saline. The plates were centrifuged (1800 rpm) at room temperature for 10 min, and 50 μl Microscint-20 was added. The plates were then sealed and read. Background activity was determined with plasma samples incubated at 4 °C. The level of inhibition was determined by comparing the readings in wells that contain compound to the readings in control wells containing DMSO.
62. Salvati, M.E.; Finlay, H.; Harikrishnan, L.S.; Jiang, J.; Johnson, J.A.; Kamau, M.G.; Lawrence, R.M.; Miller, M.M.; Qiao, J.X.; Wang, T.C.; Wang, Y.; Yang, W. PCT Int. Appl. WO 2007062314, 2007.
63. M.G. Kamau, L.S. Harikrishnan, H.J. Finlay, J.X. Qiao, J. Jiang, M.A. Poss, M.E. Salvati, R.R. Wexler, and R.M. Lawrence Tetrahedron 68 2012 2696
64. In vitro metabolic stability of compounds was determined using the following protocol: K. Kieltyka, J. Zhang, S. Li, M. Vath, C. Baglieri, C. Ferraro, T.A. Zvyaga, D.M. Drexler, H.N. Weller, and W.Z. Shou Rapid Commun. Mass Spectrom. 23 2009 1579 and references therein
65. The application of in vitro metabolic stability assays to predict in vivo metabolism and metabolic clearance of compounds in the early stages of the drug discovery process has been reported: C.A. McNaney, D.M. Drexler, S.Y. Hnatyshyn, T.A. Zvyaga, J.O. Knipe, J.V. Belcastro, and M. Sanders Assay Drug Dev. Technol. 6 2008 121
66. R.S. Obach Drug Metab. Dispos. 27 1999 1350
67. R.S. Obach, J.G. Baxter, T.E. Liston, B.M. Silber, B.C. Jones, F. Macintyre, D.J. Rance, and P.J. Wastall J. Pharmacol. Exp. Ther. 283 1997 46
68. Observed beneficial effects of fluorine in medicinal chemistry have been documented and summarized in the following references: W.K. Hagmann J. Med. Chem. 51 2008 4359
69. K. Mueller, C. Faeh, and F. Diederich Science 2007 1881 317
70. H.-J. Bohm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Muller, U. Obst-Sander, and M. Stahl Chem. Biol. Chem. 5 2004 637
71. th National Meeting of the American Chemical Society, New Orleans, LA, April 6-10, 2008; American Chemical Society: Washington, DC, 2008, MEDI-149.
72. 2:1% Dextralip 50). The tubes were centrifuged for 15-30 min at 10,000×g (10 °C), the supernatants were discarded and the pellets dissolved in 140 μL of 2% SDS. Half of the SDS solution (70 μL) was transferred to scintillation tubes, 5 mL Optifluor was added, and radioactivity measured in a scintillation counter. Background activity was determined for each sample with an aliquot incubated for 2.5 h at 4 °C. Results are reported as the amount of radioactivity transferred to endogenous LDL/VLDL, normalized by the transfer measured in the plasma sample obtained from the same animal before dosing with compound. All data are background subtracted.