Potent hypocholesterolemic activity of novel ureido phenoxyisobutyrates correlates with their intrinsic fibrate potency and not with their ACAT inhibitory activity

Journal of Lipid Research

Volumn 38, Issue 6, 1997, Pages 1189-1203

  Hawke, Roy L ^a,b   Chapman, James M ^c   Winegar, Deborah A ^b   Salisbury, Jo A ^b   Welch, Richard M ^b   Brown, Alan ^b   Franzmann, Karl W ^d   Sigel, Carl ^b  

^a UNIVERSITY OF NORTH CAROLINA   (United States)

^b GLAXOSMITHKLINE   (United States)

^c UNIVERSITY OF SOUTH CAROLINA   (United States)

^d Laboratories   (United Kingdom)

Author keywords

hydroxylase; Acyl CoA:cholesterol acyltransferase; Fibrates; Hepatocytes; VLDL + LDL cholesterol

Indexed keywords

BEZAFIBRATE; CHOLESTEROL ACYLTRANSFERASE; FIBRIC ACID DERIVATIVE; ISOBUTYRIC ACID DERIVATIVE; LOW DENSITY LIPOPROTEIN CHOLESTEROL;

ANIMAL CELL; ARTICLE; ATHEROSCLEROSIS; CHOLESTEROL METABOLISM; CORONARY RISK; CROSS LINKING; DRUG POTENCY; ENZYME ACTIVITY; ENZYME INHIBITION; HYDROXYLATION; HYPOCHOLESTEROLEMIA; LIVER CELL; NONHUMAN; PRIORITY JOURNAL; RAT;

ANIMALS; ANTILIPEMIC AGENTS; BEZAFIBRATE; BUTYRATES; CELLS, CULTURED; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; LIVER; MALE; OSMOLAR CONCENTRATION; PHENYLUREA COMPOUNDS; RATS; RATS, SPRAGUE-DAWLEY; STEROL O-ACYLTRANSFERASE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0030917135     PISSN: 00222275     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (59)

1. Illingworth, D. R., and J. A. Tobert. 1994. A review of clinical trials comparing HMG-CoA reductase inhibitors. Clin. Ther. 16: 366-385.
2. Sirtori, C. R., and G. Franceschini. 1988. Effects of fibrates on serum lipids and atherosclerosis. Pharmacol. Ther. 37: 167-191.
3. Einarsson, K., S. Ericsson, S. Ewerth, E. Reihner, M. Rudling, D. Stahlberg, and B. Angelin. 1991. Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism. Eur. J. Clin. Pharmacol. 40: S53-58.
4. Gotto, A. M. 1993. Dyslipidemia and atherosclerosis. A forecast of pharmaceutical approaches. Circulation. 87: III54-59.
5. Steinberg, D. 1986. Studies on the mechanism of action of probucol. Am. J. Cardiol. 57: 16H-21H.
6. Matsuda, K. 1994. ACAT inhibitors as antiatherosclerotic agents: compounds and mechanisms. Med. Res. Rev. 14: 271-305.
7. Tanaka, H., and T. Kimura. 1994. ACAT inhibitors in development. Exp. Opin. Invest. Drugs. 3: 427-436.
8. Suckling, K. E., and E. F. Stange. 1985. Role of acyl-CoA: cholesterol acyltransferase in cellular cholesterol metabolism. J. Lipid Res. 26: 647-671.
9. Bell, F. P. 1986. Arterial cholesterol esterification by acyl CoA:cholesterol acyltransferase: its possible significance in atherogenesis and its inhibition by drugs. In Pharmacological Control of Hyperlipidaemia. R. Fears, R. I. Levy, J. Shepard, C. J. Packard, and N. E. Miller, editors. J. R. Prous Science Publishers, Spain. 409-422.
10. Sliskovic, D. R., and A. D. White. 1991. Therapeutic potential of ACAT inhibitors as lipid lowering and anti-atherosclerotic agents. Trends Pharmacol. Sci. 12: 194-199.
11. Bocan, T. M. A., S. B. Mueller, P. D. Uhlendorf, R. S. Newton, and B. R. Krause. 1991. Comparison of CI-976, an ACAT inhibitor, and selected lipid-lowering agents for antiatherosclerotic activity in illiac-femoral and thoracic aortic lesions: Atheroscler. Thromb. 11: 1830-1843.
12. Tanaka, H., I. Ohtsuka, M. Kogushi, T. Kimura, T. Fujimori, T. Saeki, K. Hayashi, H. Kobayashi, T. Yamada, H. Hiyoshi, and I. Saito. 1994. Effect of the acyl-CoA:cholesterol acyltransferase inhibitor, E5324, on experimental atherosclerosis in rabbits. Atherosclerosis. 107: 187-210.
13. Schnitzer-Polokoff, R., D. Compton, G. Boykow, H. Davis, and R. Burrier. 1991. Effects of acyl-CoA:cholesterol O-acyltransferase inhibition on cholesterol absorption and plasma lipoprotein composition in hamsters. Comp. Biochem. Physiol. 99A: 665-670.
14. Sugiyama, Y., E. Ishikawa, H. Odaka, N. Miki, H. Tawada, and H. Ikeda. 1995. TMP-153, a novel ACAT inhibitor, inhibits cholesterol absorption and lowers plasma cholesterol in rats and hamsters. Atherosclerosis. 13: 71-78.
15. Krause, B. R., R. F. Bousley, K. A. Kieft, and R. L. Stanfield. 1992. Effect of the ACAT inhibitor CI-976 on plasma cholesterol concentrations and distribution in hamsters fed zero- and low-cholesterol diets. Clin. Biochem. 25: 371-377.
16. Largis, E. E., C. H . Wang, V. G. DeVries, and S. A. Schaffer. 1989. CL 277,082: a novel inhibitor of ACAT-catalyzed cholesterol esterification and absorption. J. Lipid Res. 30: 681-690.
17. Harris, W. S., C. A. Dujovne, K. von Bergmann, J. Neal, J. Akester, S. L. Windsor, D. Greene, and Z. Look. 1990. Effects of the ACAT Inhibitor CL 277,082 on cholesterol metabolism in humans. Clin. Pharmacol. Ther. 48: 189-194.
18. Hainer, J. W., J. G. Terry, J. M. Connell, H. Zyruk, R. M. Jenkins, D. L. Shand, P. J. Gillies, K. J. Livak, T. L. Hunt, and J. R. Crouse. 1994. Effect of the acyl-CoA:cholesterol acyltransferase inhibitor DuP 128 on cholesterol absorption and serum cholesterol in humans. Clin. Pharmacol. Ther. 56: 65-74.
19. Catapano, A. L. 1992. Mode of action of fibrates. Pharmacol. Res. 26: 331-340.
20. Lalezari, I., S. Rahbar, P. Lalezari, G. Fermi, and M. F. Perutz. 1988. LR16, a compound with potent effects on the oxygen affinity of hemoglobin, on blood cholesterol, and on low density lipoprotein. Proc. Natl. Acad. Sci. USA. 85: 6117-6121.
21. Hudson, K., S. Mojumder, and A. J. Day. 1983. The effect of bezafibrate and clofibrate on cholesterol ester metabolism in rabbit peritoneal macrophages stimulated with acetylated low density lipoproteins. Exp. Molec. Pathol. 38: 77-81.
22. Reddy, J. K., and N. D. Lalwai. 1983. Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans. Crit. Rev. Toxicol. 12: 1-58.
23. Aoyama, T., J. P. Hardwick, S. Imaoka, Y. Funae, H. V. Gelboin, and F. J. Gonzalez. 1990. Clofibrate-inducible rat hepatic P450s IVA1 and IVA3 catalyze the omega- and (omega-1)-hydroxylation of fatty acids and the omega-hydroxylation of prostaglandins E1 and F2 alpha. J. Lipid Res. 31: 1477-1482.
24. Chapman, J. M., R. L. Hawke, K. W. Franzmann, and K. J. O'Connor. 1992. Anti-atherosclerotic Aryl Compounds. W09201468 (920625 with Univ. South Carolina), Burroughs Wellcome.
25. Mor, G., and N. Lichtenstein. 1970. Inhibitors of rat liver glutaminase. Israel J. Chem. 8: 595-601.
26. Lake, B., G., T. J. B. Gray, C. R. Stubberfield, J. A. Beamand, and S. D. Gangolli. 1983. Induction of lauric acid hydroxylation and maintenance of cytochrome P-450 content by clofibrate in primary cultures of rat hepatocytes. Life Sci. 33: 249-254.
27. Heider, J. G., C. E. Pickens, and L. A. Kelly. 1983. Role of acyl-CoA:cholesterol acyltransferase in cholesterol absorption and its inhibition by 57-118 in the rabbit. J. Lipid Res. 24: 1127-1134.
28. Sedmak, J. J., and S. E. Grossberg. 1977. A rapid, sensitive, and versatile assay for protein using Coomassie Brillant Blue G250. Anal. Biochem. 79: 544-552.
29. Lalezari, I., and P. Lalezari. 1989. Synthesis and investigation of effects of 2-[4-[[(arylamino)carbonyl]amino]phenoxy]-2-methylpropionic acids on the affinity of hemoglobin for oxygen: structure-activity relationships. J. Med. Chem. 32: 2352-2357.
30. DeVries, V. G., S. A. Schaffer, E. E. Largis, M. D. Dutia, C. H. Wang, J. D. Bloom, and A. S. Katocs, Jr. 1986. An acyl-CoA:cholesterol O-acyltransferase inhibitor with hypocholesterolemic activity. J. Med. Chem. 29: 1131-1133.
31. De Vries, V. G. 1986. Antiatherosclerotic ureas and thioureas. U.S. Patent No. 4,623,662, American Cyanamid Company.
32. Abshagen, U., W. Bablok, K. Koch, P. D. Lang, H. A. E. Schmidt, M. Senn, and H. Stork. 1979. Disposition pharmacokinetics of bezafibrate in man. Eur. J. Clin. Pharmacol. 16: 31-38.
33. Woolf, T. F., S. M. Bjorge, A. E. Black, A. Holmes, and T. Chang. 1991. Metabolism of the acyl-CoA:cholesterol acyltransferase inhibitor 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide in rat and monkey. Drug Metab. Dispos. 19: 696-702.
34. Hirohashi, A., A. Nagat, H. Miyawaki, H. Nakatani, and K. Toki. 1976. Metabolism of linoleamides I. Absorption, excretion, and metabolism of N-(α-methylbenzyl)linoleamide in rat and man. Xenobiotica. 6: 329-337.
35. Fahimi, H. D., A. Reinicke, M. Sujatta, S. Yokota, M. Ozel, F. Hartig, and K. Stegmeier. 1982. The short- and long-term effects of bezafibrate in the rat. Ann. N.Y. Acad. Sci. 386: 111-113.
36. Watanabe, T., M. Mitsukawa, S. Horie, T. Suga, and K. Seki. 1987. Effects of some hypolipidemic agents on biochemical values and hepatic peroxisomal enzymes in rats: comparison of probucol, CGA, KCD-2332, MLM-160, AL-369 and clinofibrate with clofibrate. J. Pharmacobio-Dyn. 10: 142-147.
37. Azarnoff, D. L., J. K. Reddy, C. Hignite, and T. Fitzgerald. 1975. Structure activity relationships of clofibrate-like compounds on lipid metabolism. In Proceedings VI Int. Congress of Pharmacology. H. Vapaatalo, editor. IU-PHAR, Helsinki. Vol. 4: 137-147.
38. Esbenshade, T. A., V. S. Kamanna, H. A. I. Newman, V. Tortorella, D. T. Witiak, and D. R. Feller. 1990. In vivo and in vitro peroxisome proliferation properties of selected clofibrate analogues in the rat. Biochem. Pharmacol. 40: 1263-1274.
39. Eason, C. T., P. Powles, G. Henry, A. J. Spencer, A. Pattison, and F. W. Bonner. 1989. The comparative pharmacokinetics and gastric toxicity of bezafibrate and ciprofibrate in the rat. Xenobiotica. 19: 913-925.
40. Green, S., and W. Wahli. 1994. Peroxisome proliferator-activated receptors: finding the orphan a home. Mol. Cell. Endocrinol. 100: 149-153.
41. Desvergne, B., and W. Wahli. 1995. PPAR: a key nuclear factor in nutrient/gene interactions? Inducible Gene Expression. 1: 142-176.
42. Kliewer, S. A., J. M. Lenhard, T. M. Willson, I. Patel, D. C. Morris, and J. M. Lehmann. 1995. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell. 83: 813-819.
43. Forman, B. M., P. Tontonoz, J. Chen, R. P. Brun, B. M. Spiegelman, and R. M. Evans. 1995. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 83: 803-812.
44. γ). J. Biol. Chem. 270: 12953-12956.
45. Willson, T. M., J. E. Cobb, D. J. Cowan, R. W. Wiethe, I. D. Correa, S. R. Prakash, K. D. Beck, L. B. Moore, S. A. Kliewer, and J. M. Lehmann. 1996. The structure-activity relationship between peroxisome proliferator-activated receptor gamma agonism and the antihyperglycemic activity of thiazolidinediones. J. Med. Chem. 39: 665-668.
46. Aldridge, T. C., J. D. Tugwood, and S. Green. 1995. Identification and characterization of DNA elements implicated in the regulation of CYP4A1 transcription. Biochem. J. 306: 473-479.
47. Palmer, C. N., M. H. Hsu, A. S. Muerhoff, K. J. Griffin, and E. F. Johnson. 1994. Interaction of the peroxisome proliferator-activated receptor alpha with the retinoid X receptor alpha unmasks a cryptic peroxisome proliferator response element that overlaps an ARP-1-binding site in the CYP4A6 promoter. J. Biol. Chem. 269: 18083-18089.
48. Muerhoff, A. S. 1992. The peroxisome proliferator-activated receptor mediates the induction of CYP4A6, a cytochrome P450 fatty acid omega-hydroxylase, by clofibric acid. J. Biol. Chem. 267: 19051-19053.
49. Gonzalez, F. J., and D. W. Nebert. 1990. Evolution of the P450 gene superfamily: animal-plant 'warfare', molecular drive and human genetic differences in drug oxidation. Trends Genet. 6: 182-186.
50. Nelson, D. R., T. Kamataki, D. J. Waxman, P. Guengerich, R. W. Estabrook, R. Feyereisen, F. J. Gonzalez, M. J. Coon, I. C. Gunslaus, O. Gotoh, K. Okuda, and D. W. Nebert. 1993. The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol. 12: 1-15.
51. Kawashima, H., E. Kusunose, Y. Kikuta, H. Kinoshita, S. Tanaka, S. Yamamoto, T. Kishimoto, and M. Kusunose. 1994. Purification and cDNA cloning of human liver CYP4A fatty acid ω-hydroxylase. J. Biochem. 116: 74-80.
52. Staels, B., N. Vu-Dac, V. A. Kosykh, R. Saladin, J.-C. Fruchart, J. Dallongeville, and J. Auwerx. 1995. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. J. Clin. Invest. 95: 705-712.
53. Hertz, R., J. Bishara-Shieban, and J. Bar-Tana. 1995. Mode of action of peroxisome proliferators as hypolipidemic drugs: suppression of apolipoprotein C-III. J. Biol. Chem. 270: 13470-13475.
54. Haubenwallner, S., A. D. Essenburg, B. C. Barnett, M. E. Pape, R. B. DeMattos, B. R. Krause, L. L. Minton, B. J. Auerbach, R. S. Newton, T. Leff, and C. L. Bisgaier. 1995. Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action. J. Lipid Res. 36: 2541-2551.
55. Sirtori, C. R., L. Calabresi, J. P. Werba, and G. Franceschini. 1992. Tolerability of fibric acids. Comparative data and biochemical bases. Pharmacol. Res. 26: 243-260.
56. Cayen, M. N. 1985. Disposition, metabolism and pharmacokinetics of antihyperlipidemic agents in laboratory animals and man. Pharmacol. Ther. 29: 157-204.
57. Abshagen, U., S. Sporl-Radun, and J. Marinow. 1980. Steady-state kinetics of bezafibrate and clofibrate in healthy female volunteers. Eur.J. Clin. Pharmacol. 17: 305-308.
58. Wanner, C., H. Wieland, P. Schollmeyer, and W. H. Horl. 1991. Beclobrate: pharmacodynamic properties and therapeutic use in hyperlipidemia. Eur. J. Clin. Pharmacol. 40: S85-S89.
59. Davison, C., D. Benziger, A. Fritz, and J. Edelson. 1975. Absorption and disposition of 2-[4-(2,2-dichlorocyclopropyl)phenoxyl]-2-methylpropanoic acid, Win 35,833, in rats, monkeys, and men. Drug Metab. Disp. 3: 520-524.