Heterocyclic amides: Inhibitors of acyl-CoA:cholesterol O-acyl transferase with hypocholesterolemic activity in several species and antiatherosclerotic activity in the rabbit

Journal of Medicinal Chemistry

Volumn 39, Issue 20, 1996, Pages 3908-3919

  White, Andrew D ^a   Purchase II, Claude F ^a   Picard, Joseph A ^a   Anderson, Maureen K ^a   Mueller, Sandra Bak ^a   Bocan, Thomas M A ^a   Bousley, Richard F ^a   Hamelehle, Katherine L ^a   Krause, Brian R ^a   Lee, Peter ^a   Stanfield, Richard L ^a   Reindel, James F ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHOLESTEROL ACYLTRANSFERASE INHIBITOR; HYPOCHOLESTEROLEMIC AGENT;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; ATHEROSCLEROSIS; CHOLESTEROL BLOOD LEVEL; DOG; DRUG ACTIVITY; DRUG EFFICACY; ENZYME ACTIVITY; ENZYME ASSAY; HYPOCHOLESTEROLEMIA; MACROPHAGE FUNCTION; NONHUMAN; RABBIT; RAT;

ACETAMIDES; ADRENAL GLAND DISEASES; ANIMALS; ANTICHOLESTEREMIC AGENTS; ARTERIOSCLEROSIS; CHOLESTEROL; DOGS; ENZYME INHIBITORS; GUINEA PIGS; ISOXAZOLES; LIVER; MALE; MOLECULAR STRUCTURE; RABBITS; RATS; STEROL O-ACYLTRANSFERASE;

EID: 10144229124     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9604033     Document Type: Article

References (35)

1. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results. II. The Relationship of Reduction in Incidence of Coronary Heart Disease to Cholesterol Lowering. J. Am. Med. Assoc. 1984, 251, 365-373.
2. Sliskovic, D. R.; White, A. D. Therapeutic potential of ACAT inhibitors as lipid lowering and anti-atherosclerotic agents. Trends Pharmacol. Sci. 1991, 12, 194-9.
3. Scandanavian simvastatin survival study group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the scandanavian simvastatin survival study (4S). Lancet 1994, 344, 1383-1389.
4. Shephard, J. The West of Scotland Coronary Prevention Study: a trial of cholesterol reduction in Scottish men. Am. J. Cardiol 1995, 76 (9), 113c-7c.
5. Heider, J. G. Agents which inhibit cholesterol esterification in the intestine and their potential value in the treatment of hypercholesterolaemia. In Pharmalogical Control of Hyperlipidemia; Fears, R., Eds.; J. R. Prous: 1986; pp 423-438.
6. Khan, B.; Wilcox, H. G.; Heimberg, M. Cholesterol is required for secretion of very-low-density lipoprotein by rat liver, Biochem. J. 1989, 258 (3), 807-16.
7. Carr, T. P.; Hamilton Jr., R. L.; Rudel, L. L. ACAT Inhibitors Decrease Secretion of Cholesteryl esters and Apolipoprotein B by perfused livers of African Green Monkeys, J. Lipid Res. 1995, 36, 25-36.
8. Bell, F. P. Arterial cholesterol esterification by acyl CoA cholesterol acyltransferase: its possible significance in atherogenesis and its inhibition by drugs. In Pharmacological control of hyperlipidemia, Fears, R., Eds.; J. R. Prous: Barcelona, 1986; pp 409.
9. Peck, R. W.; Wiggs, R.; Posner, J. The tolerability, pharmaco-kinetics and lack of effect on plasma cholesterol of 447C88, an AcylCoA:Cholesterol Acyl Transferase (ACAT) inhibitor with low bioavailability, in healthy volunteers. Eur. J. Clin. Pharmacol. 1995, 49, 243-249.
10. Harris, W. S.; Dujovne, C. A.; von-Bergmann, K.; Neal, J.; Akester, J.; Windsor, S. L.; Greene, D.; Look, Z. Effects of the ACAT inhibitor CL 277,082 on cholesterol metabolism in humans. Clin. Pharmacol. Ther. 1990, 48, 189-94.
11. Hainer, J. W.; Terry, J. G.; Connell, J. M.; Zyruk, H.; Jenkins, R. M.; Shand, D. L.; Gillies, P. J.; Livak, K. J.; Hunt, T. L.; et al. Effect of the acyl-CoA:cholesterol acyltransferase inhibitor DuP 128 on cholesterol absorption and serum cholesterol in humans. Clin. Pharmacol. Ther 1994, 56 (1), 65-74.
12. Roth, B. D.; Blankley, C. J.; Hoefle, M. L.; Holmes, A.; Roark, W. H.; Trivedi, B. K.; Essenburg, A. D.; Kieft, K. A.; Krause, B. R.; Stanfield, R. L. Inhibitors of acyl-CoA:cholesterol acyltransferase. 1. Identification and structure-activity relationships of a novel series of fatty acid anilide hypocholesterolemic agents. J. Med. Chem. 1992, 35, 1609-17.
13. Roark, W. H.; Roth, B. D.; Holmes, A.; Trivedi, B. K.; Kieft, K. A.; Essenburg, A. D.; Krause, B. R.; Stanfield, R. L. Inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT). 2. Modification of fatty acid anilide ACAT inhibitors: bioisosteric replacement of the amide bond. J. Med. Chem. 1993, 36, 1662-8.
14. Trivedi, B. K.; Holmes, A.; Stoeber, T. L.; Blankley, C. J.; Roark, W. H.; Picard, J. A.; Shaw, M. K.; Essenburg, A. D.; Stanfield, R. L.; Krause, B. R. Inhibitors of acyl-CoA:cholesterol acyltransferase. 4. A novel series of urea ACAT inhibitors as potential hypocholesterolemic agents. J. Med. Chem. 1993, 36, 3300-7.
15. Augelli-Szafran, C. E.; Blankley, C. J.; Roth, B. D.; Trivedi, B. K.; Bousley, R. F.; Essenburg, A. D.; Hamelehle, K. L.; Krause, B. R.; Stanfield, R. L. Inhibitors of acyl-CoA:cholesterol acyltransferase. 5. Identification and structure-activity relationships of novel beta-ketoamides as hypocholesterolemic agents. J. Med. Chem. 1993, 36, 2943-9.
16. Trivedi, B. K.; Purchase, T. S.; Holmes, A.; Augelli-Szafran, C. E.; Essenburg, A. D.; Hamelehle, K. L.; Stanfield, R. L.; Bousley, R. F.; Krause, B. R. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activity. J. Med. Chem. 1994, 37, 1652-9.
17. O'Brien, P. M.; Sliskovic, D. R.; Blankley, C. J.; Roth, B. D.; Wilson, M. W.; Hamelehle, K. L.; Krause, B. R.; Stanfield, R. L. Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 8. Incorporation of amide or amine functionalities into a series of disubstituted ureas and carbamates. Effects on ACAT inhibition in vitro and efficacy in vivo. J. Med. Chem. 1994, 37, 1810-22.
18. Bocan, T. M.; Mueller, S. B.; Uhlendorf, P. D.; Newton, R. S.; Krause, B. R. Comparison of CI-976, an ACAT inhibitor, and selected lipid-lowering agents for antiatherosclerotic activity in iliac-femoral and thoracic aortic lesions. A biochemical, morphological, and morphometric evaluation. Arterioscler. Thromb. 1991, 11, 1830-43.
19. O'Brien, P. M.; Sliskovic, D. R.; Bernabei, A.; Hurley, T.; Anderson, M. K.; Bousley, R. F.; Krause, B. R.; Stanfield, R. L. Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 13. Design, synthesis and biological evaluation of tetrazole anilides as potent inhibitors of ACAT in vitro and hypocholesterolemic agents in vivo. Bioorg. Med. Chem. Lett. 1995, 5 (3), 295-300.
20. Seki, K.; Isegawa, J.; Fukuda, M.; Ohki, M. Studies on hypolipidemic agents. II. Synthesis and pharmacological properties of alkylpyrazole derivatives, Chem. Pharm. Bull. 1984, 32 (4), 1568-77.
21. Micetich, R. G. Lithiation of five-membered heteroaromatic compounds. Methyl substituted 1,2-azoles, oxadiazoles, and thiadiazoles. Can. J. Chem. 1970, 48 (13), 2006-15.
22. Kanemasa, S.; Tsuge, O. Recent advances in synthetic applications of nitrile oxide cycloaddition (1981-1989), 1990.
23. Mukaiyama, T.; Hoshino, T. The reactions of primary nitroparaffins with isocyanates. J. Am. Chem. Soc. 1960, 82, 5339.
24. Birch, A. J.; Walker, K. A. M. Aspects of Catalytic Hydrogenation with a Soluble Catalyst. J. Chem. Soc. C 1966, 1894-96.
25. Hetzheim, A.; Mockel, K. Recent Advances in 1,3,4-Oxadiazole Chemistry. In Advances in Heterocyclic Chemistry, Katritzky, A. R., Boulton, A. J., Eds.; Academic Press: New York, 1966; Vol. 20, pp 183-186.
26. Clapp, L. B. 1,2,4-Oxadiazoles. In Advances in Heterocyclic Chemistry, Katritzky, A. R., Boulton, A. J., Eds.; Academic Press: New York, 1976; Vol. 20, pp 65-69.
27. Hata, T.; Mukaiyama, T. The Dehydration Reactions by Means of Esters of Phosphoric Acid. Bull. Chem. Soc. Jpn. 1961, 34 (1), 99-101.
28. Kelley, J. L.; Miller, C. A.; McLean, E. W. Attempted inhibition of histidine decarboxylase with β-alkyl analogs of histidine, J. Med. Chem 1977, 20, 721-3.
29. Birkofer, L.; Wegner, P. 1.3-Cycloadditionen mit Trimethylsilylazid; uber isomere N-Acetyl-1.2.3-triazole. Chem. Ber 1966, 99, 3485-94.
30. Krause, B. R.; Black, A.; Bousley, R.; Essenburg, A.; Cornicelli, J.; Holmes, A.; Homan, R.; Kieft, K.; Sekerke, C.; Shaw-Hes, M. K.; et al. Divergent pharmacologic activities of PD 132301-2 and CL 277,082, urea inhibitors of acyl-CoA: cholesterol acyltransferase. J. Pharmacol. Exp. Ther. 1993, 267, 734-43.
31. Lowry, O. H.; Rosebrough, N. J.; Farr, A. L.; Randell, R. J. Protein Measurement with the Folin Reagent. J. Biol. Chem. 1951, 193, 265-275.
32. Dominick, M. A.; McGuire, E. J.; Reindel, J. F.; Bobrowski, W. F.; Bocan, T. M.; Gough, A. W. Subacute toxicity of a novel inhibitor of acyl-CoA: cholesterol acyltransferase in beagle dogs. Fundam. Appl. Toxicol. 1993, 20, 217-24.
33. O'Brien, P. M.; Sliskovic, D. R.; Anderson, M. K.; Bousley, R. F.; Krause, B. R.; Stanfield, R. L. Inhibitors of acyl-CoA: cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 12. Syntheses and biological activity of structurally novel tetrazole amides. Bioorg. Med. Chem. Lett. 1995, 5 (3), 289-94.
34. O'Brien, P. M.; Sliskovic, D. R.; Picard, J. P.; Lee, H. T.; Purchase, Claude F., II; Roth, B. D.; White, A. D.; Anderson, M. K.; Bak Mueller, S.; Bocan, T. M. A.; Bousley, R. F.; Hamelehle, K. L.; Homan, R.; Krause, B. R.; Lee, P.; Reindel, J. F.; Stanfield, R. L.; Turlock, D. Inhibitors of Acyl-CoA: cholesterol O-Acyl-transferase (ACAT). Synthesis and Pharmacological Activity of (±)-2-Dodecyl-α-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5- acetamide and Structurally Related Tetrazole Amide Derivatives. J. Med. Chem. 1996, 39, 2354-2366.
35. White, A. D.; Blankley, C. J.; Essenburg, A. D.; Stanfield, R. L.; Creswell, M. W.; Wilson, M. W.; Hamelehle, K. L.; Dominick, M. A.; Chucholowski, A. W.; Bonsley, R. F.; Krause, B. R.; Neub, M. Heterocyclic Ureas - Inhibitors of Acyl-CoA:cholesterol acyl transferase as Hypocholesterolemic agents. J. Med. Chem., in press.