Long hydrocarbon chain keto diols and diacids that favorably alter lipid disorders in vivo

Journal of Medicinal Chemistry

Volumn 47, Issue 24, 2004, Pages 6082-6099

  Mueller, Ralf ^a   Yang, Jing ^a   Duan, Caiming ^a   Pop, Emil ^a   Geoffroy, Otto J ^a   Zhang, Lian Hao ^a   Huang, Tian Bao ^a   Denisenko, Sergey ^a   McCosar, Bruce H ^a   Oniciu, Daniela C ^b   Bisgaier, Charles L ^b   Pape, Michael E ^b   Freiman, Catherine Delaney ^b   Goetz, Brian ^b   Cramer, Clay T ^b   Hopson, Krista L ^b   Dasseux, Jean Louis H ^b  

^a Alchem Laboratories Corporation   (United States)

^b Esperion Therapeutics Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,13 DIHYDROXY 2,2,12,12 TETRAMETHYLTRIDECAN 7 ONE; 2,2,14,14 TETRAMETHYL 8 OXOPENTADECANEDIOIC ACID; 7 OXO 2,2,12,12 TETRAMETHYLTRIDECANEDIOIC ACID; ANTILIPEMIC AGENT; DICARBOXYLIC ACID DERIVATIVE; FATTY ACID; GLUCOSE; GLYCOL; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; INSULIN; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL MODEL; ARTICLE; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; DIABETIC OBESITY; DOSE RESPONSE; DRUG EFFICACY; DRUG SYNTHESIS; DYSLIPIDEMIA; FATTY ACID BLOOD LEVEL; FEMALE; GLUCOSE BLOOD LEVEL; IN VITRO STUDY; IN VIVO STUDY; INSULIN BLOOD LEVEL; LIPOGENESIS; LIVER CELL CULTURE; METABOLIC SYNDROME X; MOLECULAR SIZE; NONHUMAN; RAT; RAT STRAIN; STRUCTURE ACTIVITY RELATION; TRIACYLGLYCEROL BLOOD LEVEL;

ALCOHOLS; ANIMALS; ANTILIPEMIC AGENTS; CELLS, CULTURED; CHOLESTEROL, HDL; DIABETES MELLITUS; DICARBOXYLIC ACIDS; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; HEPATOCYTES; HYDROCARBONS; HYPERLIPIDEMIAS; KETO ACIDS; KETONES; LIPIDS; MALE; METABOLIC DISEASES; RATS; RATS, SPRAGUE-DAWLEY; RATS, ZUCKER;

EID: 8644252683     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm040006p     Document Type: Article

References (64)

1. Hubert, H. B.; Eaker, E. D.; Garrison, R. J.; Castelli, W. P. Life-style correlates of risk factor change in young adults: An eight-year study of coronary heart disease risk factors in the Framingham offspring. Am. J. Epidemiol. 1987, 125, 812-831. Erratum: Am. J. Epidemiol. 1987, 126, 559.
2. Gotto, A. M., Jr. Management of dyslipidemia. Am. J. Med. 2002, 112, Suppl. 8A, 10S-18S.
3. Luc, G.; Bard, J. M.; Ferrieres, J.; Evans, A.; Amouyel, P.; Arveiler, D.; Fruchart, J. C.; Ducimetiere, P.; Value of HDL cholesterol, apolipoprotein A-I, lipoprotein A-I, and lipoprotein A-I/A-II in prediction of coronary heart disease: The PRIME study. Arterioscler. Thromb. Vasc. Biol. 2002, 22, 1155-161.
4. Gotto, A. M., Jr. Triglyceride as a risk factor for coronary artery disease. Am. J. Cardiol. 1998, 82, 22Q-25Q.
5. Sprecher, D. L. Triglycerides as a risk factor for coronary artery disease. Am. J. Cardiol. 1998, 82, 49U-56U; discussion 85U-86U.
6. Assmann, G.; Schulte, H.; Funke, H.; von Eckardstein, A. The emergence of triglycerides as a significant independent risk factor in coronary artery disease. Eur. Heart J. 1998, 19 Suppl M, M8-14.
7. Bloch, K. The biological synthesis of cholesterol. Science 1965, 150, 19-28.
8. Brown, M. S.; Goldstein, J. L. A receptor-mediated pathway for cholesterol homeostasis. Science 1986, 232, 34-47.
9. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian simvastatin survival study (4S). Lancet 1994, 344, 1383-1389.
10. Frick, M. H.; Elo, O.; Haapa, K.; Heinonen, O. P.; Heinsalmi, P.; et al. Helsinki Heart Study: Primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N. Engl. J. Med. 1987, 317, 1237-1245.
11. 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. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: A randomized controlled trial. JAMA 2001, 285, 1585-1591.
12. Bloomfield Rubins, H.; Davenport, J.; Babikian, V.; Brass, L. M.; Collins, D.; et al. Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT). Circulation 2001, 103, 2828-2833.
13. Sircar, I.; Hoefle, M.; Maxwell, R. E. Phenylenebis(oxy)bis[2,2- dimethylpentanoic acid]s: Agents that elevate high-density lipoproteins. J. Med. Chem. 1983, 26, 1020-1027.
14. Bar-Tana, J.; Ben-Shoshan, S.; Blum, J.; Migron, Y.; Hertz, R.; Pill, J.; Rose-Kahn, G.; Witte, E. C. Synthesis and hypolipidemic and antidiabetogenic activities of β,β,β′,β′-tetrasubstituted, long-chain dioic acids. J. Med. Chem. 1989, 32, 2072-2084.
15. Bar-Tana, J. Carboxylic acids and derivatives thereof and pharmaceutical compositions. WO 9900116 A2, 1999.
16. Mayorek, N.; Kalderon, B.; Itach, E.; Bar-Tana, J. Sensitization to insulin induced by beta,beta′-methyl-substituted hexadecanedioic acid (MEDICA 16) in obese Zucker rats in vivo. Diabetes 1997, 46, 1958-1964.
17. Russell, J. C.; Amy, R. M.; Graham, S. E.; Dolphin, P. J.; Wood, G. O.; Bar-Tana, J. Inhibition of atherosclerosis and myocardial lesions in the JCR:LA-cp rat by β,β′-tetramethylhexadecanedioic acid (MEDICA 16). Arterioscler. Thromb. Vasc. Biol. 1995, 15, 918-923.
18. Frenkel, B.; Bishara-Shieban, J.; Bar-Tana, J. The effect of β,β-tetramethylhexadecanedioic acid (MEDICA 16) on plasma very-low-density lipoprotein metabolism in rats: Role of apolipoprotein C-III. Biochem. J. 1994, 298, 409-414.
19. Hertz, R.; Bar-Tana, J.; Sujatta, M.; Pill, J.; Schmidt, F. H.; et al. The induction of liver peroxisomal proliferation by β,β′-methyl- substituted hexadecanedioic acid (MEDICA 16). Biochem. Pharmacol. 1988, 37, 3571-3577.
20. Berge, R. K.; Aarsland, A.; Kryvi, H.; Bremer, J.; Aarsaether, N. Alkylthio acetic acids (3-thia fatty acids) - A new group of nonbeta-oxidizable peroxisome-inducing fatty acid analogues-II. Dose-response studies on hepatic peroxisomal- and mitochondrial changes and long-chain fatty acid metabolizing enzymes in rats. Biochem. Pharmacol. 1989, 38, 3969-3979.
21. Aarsland, A.; Aarsaether, N.; Bremer, J.; Berge, R. K. Alkylthioacetic acids (3-thia fatty acids) as nonbeta-oxidizable fatty acid analogues: A new group of hypolipidemic drugs. III. Dissociation of cholesterol- and triglyceride-lowering effects and the induction of peroxisomal beta-oxidation. J. Lipid Res. 1989, 30, 1711-1718.
22. Berge, R. K.; Aarsland, A.; Kryvi, H.; Bremer, J.; Aarsaether, N. Alkylthioacetic acid (3-thia fatty acids) - A new group of nonbeta-oxidizable, peroxisome-inducing fatty acid analogues. I. A study on the structural requirements for proliferation of peroxisomes and mitochondria in rat liver. Biochim. Biophys. Acta 1989, 1004, 345-356.
23. Berge, R. K.; Skorve, J.; Tronstad, K. J.; Berge, K.; Gudbrandsen, O. A.; et al. Metabolic effects of thia fatty acids. Curr. Opin. Lipidol. 2002, 13, 295-304.
24. Bisgaier, C. L.; Essenburg, A. D.; Barnett, B. C.; Auerbach, B. J.; Haubenwallner, S.; et al. A novel compound that elevates high-density lipoprotein and activates the peroxisome proliferator activated receptor. J. Lipid Res. 1998, 39, 17-30.
25. Bisgaier, C. L.; Creger, P. L.; Saltiel, A. R.; Tafuri, S. R. Carboxyalkylethers, formulations, and treatment of vascular diseases, U.S. patent 5,756,544, May 26, 1998.
26. Bays, H. E.; McKenney, J. M.; Dujovne, C. A.; Schrott, H. G.; Zema, M. J.; Nyberg, J.; MacDougall, D. E. effectiveness and tolerability of a new lipid-altering agent, Gemcabene, in patients with low levels of high-density lipoprotein cholesterol. Am. J. Cardiol. 2003, 92, 538-543.
27. (a) Dasseux, J.-L. H.; Oniciu, D. C. Methods for synthesizing ether compounds and intermediates therefor, U.S. patent 6,410,802 B1, June 25, 2002.
28. (b) Dasseux, J.-L. H. Methods of treating cardiovascular diseases, dyslipidemia, dyslipoproteinemia, and hypertension with ether compounds, U.S. patent 6,506,799 B1, January 14, 2003.
29. (c) Mueller, R.; Yang, J.; Duan, C.; Pop, E.; Zhang, L. H.; Huang, T.-B.; Denisenko, A.; Denisko, O. V.; Oniciu, D. C.; Bisgaier, C. L.; Pape, M. E.; Freiman, C. D.; Goetz, B; Cramer, C. T.; Hopson, K. L.; Dasseux, J.-L. H. Long Hydrocarbon Chain Ether Diols and Ether Diacids That Favorably Alter Lipid Disorders in Vivo. J. Med. Chem. 2004, 47, 5183-5197.
30. (d) Cramer, C. T.; Goetz, B.; Hopson. K. L. M.; Fici, G. J.; Ackermann, R. M.; Brown, S. C.; Bisgaier, C. L.; Rajeswaran, W. G.; Oniciu, D. C.; Pape, M. E. Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome. J. Lipid Res. 2004, 45, 1289-1301.
31. Bar-Tana, J.; Rose-Kahn, G.; Srebnik, M. Inhibition of lipid synthesis by β,β′-tetramethyl-substituted, C14-C22, α,ω- dicarboxylic acids in the rat in vivo. J. Biol. Chem. 1985, 260, 8404-8410.
32. Bremer, J. The biochemistry of hypo- and hyperlipidemic fatty acid derivatives: Metabolism and metabolic effects. Prog. Lipid Res. 2001, 40, 231-268.
33. Russell, J. C.; Dolphin, P. J.; Hameed, M.; Stewart, B.; Koeslag, D. G.; et al. Hypolipidemic effect of β,β′-tetramethyl hexadecanedioic acid (MEDICA 16) in hyperlipidemic JCR:LA-corpulent rats. Arterioscler. Thromb. 1991, 11, 602-609.
34. Dasseux, J.-L. H.; Oniciu, D. C. Ketone compounds and compositions for cholesterol management and related uses. U.S. patent application 20030078239, Oct. 11, 2001.
35. (a) Possel, O.; van Leusen, A. M. Tosylmethyl isocyanide employed in a novel synthesis of ketones. A new masked formaldehyde reagent. Tetrahedron Lett. 1977, 17, 4229-4232.
36. 2- Bridges. Tetrahedron Lett. 1982, 23, 5335-5338.
37. (c) Yadav, J. S.; Gadgil, V. R. TosMIC in the preparation of spiroacetals: Synthesis of pheromone components of olive fruit fly. Tetrahedron Lett. 1990, 31, 6217-6218.
38. van Leusen, D.; van Leusen, A. M. Synthetic uses of tosylmethyl isocyanide (TosMIC). In Organic Reactions; Overman, L. E., Ed.; John Wiley and Sons: New York, 2001; Vol. 57, pp 417-666.
39. Shiner, V. J., Jr.; Smith, M. L. The Arrhenius parameters of the deuterium isotope rate effect in a base-promoted elimination reaction: Evidence for proton tunneling. J. Am. Chem. Soc. 1961, 83, 593-598.
40. (a) Ghosh, S.; Pardo, S. N.; Salomon, R. G. Ester Enolates from α-Acetoxy Esters. Synthesis of Aryl Malonic and α-Aryl Alkanoic Esters from Aryl Nucleophiles and α-Keto Esters. J. Org. Chem. 1982, 47, 4692-4702.
41. (b) Chounan, Y.; Ono, Y.; Nishii, S.; Kitahara, H.; Ito, S.; Yamamoto, Y. 1,2-Asymmetric induction in the conjugate addition of organocopper reagents to γ-aryl α,β-unsaturated carbonyl derivatives. Tetrahedron 2000, 56, 2821-2831.
42. (a) Ackerley, N.; Brewster, A. G.; Brown, G. R.; Clarke, D. S.; Foubister, A. J.; Griffin, S. J.; Hudson, J. A.; Smithers, M. J.; Whittamore, P. R. O. A novel approach to dual-acting thromboxane receptor antagonist/synthase inhibitors based on the link of 1,3-dioxane-thromboxane receptor antagonists and -thromboxane synthase inhibitors. J. Med. Chem. 1995, 38, 1608-1628.
43. (b) Manley, P. W.; Tuffin, D. P.; Allanson, N. M.; Buckle, P. E.; Lad, N.; Lai, S. M. F.; Lunt, D. O.; Porter, R. A.; Wade, P. J. Thromboxane synthase inhibitors. Synthesis and pharmocological activity of (R)-, (S)-, and (±)-2,2-dimethyl-6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)-methoxy] ethoxy]hexanoic acids. J. Med. Chem. 1987, 30, 1812-1818.
44. (a) Brown, H. C.; Narasimhan, S.; Choi, Y. M. Selective reductions. 30. Effect of cation and solvent on the reactivity of saline borohydrides for reduction of carboxylic esters. Improved procedures for the conversion of esters to alcohols by metal borohydrides. J. Org. Chem. 1982, 47, 4702-4708.
45. (b) Soai, K.; Ookawa, A. Mixed solvents containing MeOH as useful reaction media for unique chemoselective reductions with lithium borohydride. J. Org. Chem. 1986, 51, 4000-4005.
46. 4 depended on the conditions. In ether at room temperature the bromo alcohol was the single product, whereas in THF at reflux the reaction gave the alcohols exclusively. See: Beckwith, A. L. J.; Raner, K. D. Stereochemistry of the reversible cyclization of ω-formyl radicals. J. Org. Chem. 1992, 57, 4954-4962.
47. 4I but required a slightly longer reaction time.
48. (a) Stevens, R. V.; Chapman, K. T.; Stubbs, C. A.; Tam, W. W.; Albizati, K. F. Further studies on the utility of sodium hypochlorite in organic synthesis. Selective oxidation of diols and direct conversion of aldehydes to esters. Tetrahedron Lett. 1982, 23, 4647-4650.
49. (b) Stevens, R. V.; Chapman, K. T.; Weller, H. N. Convenient and inexpensive procedure for oxidation of secondary alcohols to ketones. J. Org. Chem. 1980, 45, 2030-2032.
50. Hatch, R. P.; Shringarpure, J.; Weinreb, S. M. Studies on total synthesis of the olivomycins. J. Org. Chem. 1978, 43, 4172-4177.
51. Prato, M.; Quintily, U.; Scorrano, G.; Sturaro, A. Cleavage of the 1,3-dithiane protective group. Synthesis 1982, 679-680.
52. For similar successive alkylations of TosMIC with alkyl halides of different chain lengths, see: (a) ref 32c; (b) Rao, A. V. R.; Deshpande, V. H.; Reddy, S. P. A new route for the synthesis of 1,4-dicarbonyl compounds: Synthesis of jasmone, dihydrojasmone and a prostaglandin intermediate. Synth. Commun. 1984, 14, 469-475.
53. For similar successive alkylations of TosMIC with alkyl halides of different chain lengths, see: (a) ref 32c; (b) Rao, A. V. R.; Deshpande, V. H.; Reddy, S. P. A new route for the synthesis of 1,4-dicarbonyl compounds: Synthesis of jasmone, dihydrojasmone and a prostaglandin intermediate. Synth. Commun. 1984, 14, 469-475.
54. For similar monoalkylations of TosMIC with long chain bromo esters, see: Johnson. D. W. A Synthesis of unsaturated very long chain fatty acids. Chem. Phys. Lipids 1990, 56, 65-71.
55. Vedejs, E.; Dent, W. H., III; Gapinski, D. M.; McClure, C. K. Local conformer effects in unsaturated lactones. J. Am. Chem. Soc. 1987, 109, 5437-5446.
56. Shultz, D. A.; Fox, M. A. The effect of phenyl ring torsional rigidity on the photophysical behavior of tetraphenylethylenes. J. Am. Chem. Soc. 1989, 111, 6311-6320.
57. Stütz, P.; Stadler, P. A. 3-Alkylated and 3-acylated indoles from a common precursor: 3-Benzylindole and 3-benzoylindole. In Organic Syntheses; Noland, W. E., Editor-in-Chief; John Wiley and Sons: New York, 1988; Collect. Vol. VI, pp 109-114.
58. Beynen, A. C.; Geelen, M. J. Short-term inhibition of fatty acid biosynthesis in isolated hepatocytes by mono-aromatic compounds. Toxicology 1982, 24, 183-197.
59. Bottomley, S.; Garcia-Webb, P. Rat hepatocyte lipogenesis and insulin-stimulated lipogenesis: Comparison of metabolite effects and methods of measurement. Biochem. Int. 1987, 14, 751-758.
60. Bisgaier, C. L.; Essenburg, A. D.; Auerbach, B. J.; Pape, M. E.; Sekerke, C. S.; Gee, A.; Wolle, S.; Newton, R. S. Attenuation of plasma low-density lipoprotein cholesterol by select 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in mice devoid of low-density lipoprotein receptors. J. Lipid Res. 1997, 38(12), 2502-15.
61. Seglen, P. O. Hepatocyte suspensions and cultures as tools in experimental carcinogenesis. J. Toxicol. Environ. Health 1979, 5, 551-560.
62. Kieft, K. A.; Bocan, T. M.; Krause, B. R. Rapid on-line determination of cholesterol distribution among plasma lipoproteins after high-performance gel filtration chromatography. J. Lipid Res. 1991, 32, 859-866.
63. Kuwahara, M.; Kawano, Y.; Kajino, M.; Ashida, Y.; Miyake, A. Synthetic Studies on Condensed-Azole Derivatives. V. Synthesis and anti-asthmatic activities of ω-sulfamoylalkyloxy[l,2,4]-triazolo[1,5-b]pyridazines. Chem. Pharm. Bull. 1997, 45, 1447-1457.
64. Banfi, S.; Montanari, F.; Pozzi, G.; Quici, S. Catalysts for alkene epoxidation by hydrogen peroxide: Synthesis and activity of a tailed chiral Mn(III)-tetraaryl-porphyrin bearing a covalently bonded carboxylic group. Gazz. Chim. Ital. 1993, 123, 617-621.