α-substituted malonester amides: Tools to define the relationship between ACAT inhibition and adrenal toxicity

Journal of Medicinal Chemistry

Volumn 41, Issue 5, 1998, Pages 682-690

  Sliskovic, Drago R ^a,b   Picard, Joseph A ^a,b   O'Brien, Patrick M ^a,b   Liao, Peggy ^a,b   Howard Roark, W ^a,b   Roth, Bruce D ^a,b   Anderson, Maureen A ^a,b   Mueller, Sandra Bak ^a,b   Bocan, Thomas M A ^a,b   Bousley, Richard F ^a,b   Hamelehle, Katherine L ^a,b   Homan, Reynold ^a,b   Reindel, James F ^a,b   Stanfield, Richard L ^a,b   Turluck, Daniel ^a,b   Krause, Brian R ^a,b  

^a PFIZER INC   (United States)

^b Department of Medicinal Chemistry ^*

Author keywords

[No Author keywords available]

Indexed keywords

CHOLESTEROL; CHOLESTEROL ACYLTRANSFERASE; CHOLESTEROL ACYLTRANSFERASE INHIBITOR;

ADRENAL DISEASE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BIOASSAY; DOG; DRUG ACTIVITY; DRUG BLOOD LEVEL; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; GUINEA PIG; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; LIVER MICROSOME; MALE; MOUSE; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT; ULTRAVIOLET SPECTROSCOPY;

ADRENAL GLANDS; AMIDES; ANIMALS; ANTICHOLESTEREMIC AGENTS; BIOLOGICAL AVAILABILITY; CHOLESTEROL; CHOLESTEROL, DIETARY; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DOGS; ENZYME INHIBITORS; FEMALE; GUINEA PIGS; MALE; MALONATES; MICE; MICROSOMES, LIVER; NECROSIS; PHENYLACETATES; RATS; RATS, SPRAGUE-DAWLEY; STEROL O-ACYLTRANSFERASE; TETRAZOLES;

EID: 15644364732     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970560h     Document Type: Article

References (27)

1. (a) Moreno, P. R.; Falk, E.; Palacios, I. F.; Newell, J. B.; Fuster, V.; Fallon, J. T. Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation 1994, 90, 775-778.
2. (b) Galis, Z. S.; Sukhova, G. K.; Kranzhofer, R.; Clark, S.; Libby, P. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc. Natl Acad. Sci. U.S.A. 1995, 92, 402-406.
3. (c) Maher, V. M. G. Coronary atherosclerosis stabilization: An achievable goal. Atherosclerosis 1995, 118, S91-S101.
4. (d) 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., Ed.; J. R. Prous Science Publishers, SA: Barcelona, 1986; pp 409-422.
5. Sliskovic, D. R.; Trivedi, B. K. ACAT Inhibitors: Potential Antiatherosclerotic Agents. Curr. Med. Chem. 1994, 1, 204-225.
6. Roth, B. D. ACAT Inhibitors: Evolution from Cholesterol- Absorption Inhibitors to Anti-atherosclerotic Agents. Drug Discovery Today 1998, 3, 19-25.
7. Sliskovic, D. R.; Picard, J. A.; Roark, W. H.; Essenburg, A. D.; Krause, B. R.; Minton, L. L.; Reindel, J. F.; Stanfield, R. L. Inhibitors of Acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. The synthesis and biological activity of a series of malonester amides. Bioorg. Med. Chem. Lett. 1996, 6, 713-718.
8. Vliet, E. B.; Marvel, C. S.; Hsueh, C. M. 3-Methylpentanoic acid. Org. Synth. 1943, 2, 416-417.
9. Krause, B. R.; Black, A.; Bousley, R.; Essenburg, A. D.; Cornicelli, J. A.; Holmes, A.; Homan, R.; Kieft, K. A.; Sekerke, C.; Shaw- Hes, M. K.; Stanfield, R. L.; Trivedi, B. K.; Woolf, T. Divergent Pharmacological Activities of PD 132301-2 and CL 277,082, Urea Inhibitors of Acyl CoA:Cholesterol Acyl-Transferase. J. Pharmacol. Exp. Ther. 1993, 267, 734-743.
10. White, A. D.; Purchase II, C. F.; Picard, J. A.; Anderson, M. K.; Bak Mueller, S.; Bocan, T. M. A.; Bousley, R. F.; Hamelehle, K. L.; Krause, B. R.; Lee, P.; Stanfield, R. L.; Reindel, J. F. Heterocyclic Amides: Inhibitors of Acyl-CoA:Cholesterol OAcyltransferase with hypocholesterolemic activity in several species and antiatherosclerotic activity in the rabbit. J. Med. Chem. 1996, 39, 3908-3919.
11. 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-Co A:Cholesterol Acyltransferase. 1. Identification and Structure-Activity Relationships of a Novel Series of Fatty Acid Anilide Hypocholesterolemic Agents. J. Med. Chem. 1992, 35, 1609-1617.
12. O'Brien, P. M.; Sliskovic, D. R.; Picard, J. A.; Lee, H. T.; Purchase II, C. F.; Roth, B. D.; White, A. D.; Anderson, M. K.; Bak Mueller, S.; Bocan, T. M. A.; Bousley, R. F.; Hamelehle, K. L.; Homan, R.; Lee, P.; Krause, B. R.; Lee, P.; Reindel, J. F.; Stanfield, R. L.; Turluck, D. Inhibitors of Acyl-Co A:Cholesterol O-Acyltransferase. Synthesis and pharmacological activity of (±)-2-dodecyl-α-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5- acetamide and structurally related tetrazole derivatives. J. Med. Chem. 1996, 39, 2354-2366.
13. Dominick, M. A.; Bobrowski, W. A.; MacDonald, J. R.; Gough, A. W. Morphogenesis of a zone-specific adrenocortical cytotoxicity in guinea pigs administered PD 132301-2, an inhibitor of acylCoA:cholesterol O-acyltransferase. Toxicol. Pathol. 1993, 21, 54-62.
14. Wolfgang, G. H. I.; Robertson, D.G.; Welty, D. F.; Metz, A. L. Hepatic and adrenal toxicity of a novel lipid regulator in beagle dogs. Fundam. Appl. Toxicol. 1995, 26, 272-281.
15. 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- 1659.
16. Dominick, M. A.; McGuire, E. J.; Reindel, J. F.; Bobrowski, W. A.; Bocan, T. M. A.; Gough, A. W. Subacute toxicity of a novel inhibitor of acyl-CoA:cholesterol acyltransferase in beagle dogs. Fundam. Appl. Toxicol. 1993, 20, 217-224.
17. Vernetti, L. A.; MacDonald, J. R.; Wolfgang, G. H. I.; Dominick, M. A.; Pegg, D. G. ATP Depletion is associated with cytotoxicity of a novel lipid regulator in guinea pig adrenocortical cells. Toxicol. Appl. Pharmacol. 1993, 118, 30-38.
18. Riddell, D.; Bright, C. P.; Burton, B. J.; Bush, R. C.; Harris, N. V.; Hele, D.; Moore, U. M.; Naik, K.; Parrott, D. P.; Smith, C.; Williams, R. J. Hypolipidemic properties of a potent and bioavailable alkylsulphinyl-diphenylimidazole ACAT inhibitor (RP 73163) in animals fed diets low in cholesterol. Biochem. Pharmacol. 1996, 52, 1177-1186.
19. Albaladejo, V.; Catinot, R.; Moronvalle-Halley, V.; Kriszt, W.; Schorsch, F.; Picaut, P.; Baron, H.; Ballet, F. RP 73163, A novel systemic ACAT-inhibitor induces coarse vacuolation and impairs steroid hormone metabolism in guinea pig adrenocortical cells. Book of Abstracts-EUROTOX '94, p 3.
20. Matsuo, M.; Ito, F.; Konto, A.; Aketa, M.; Tomoi, M.; Shimomura, K. Effect of FR 145237, a novel ACAT inhibitor, on atherogenesis in cholesterol-fed and WHHL rabbits. Evidence for a direct effect on the arterial wall. Biochim. Biophys. Acta 1995, 1259, 254- 260.
21. Matsuo, M.; Hashimoto, M.; Suzuki, J.; Iwanami, K.; Tomoi, M.; Shimomura, K. Difference between normal and WHHL rabbits in susceptibility to the adrenal toxicity of an acyl-CoA:cholesterol acyltransferase inhibitor, FR 145237. Toxicol. Appl. Pharmacol. 1996, 140, 387-392.
22. Wilde, R. G.; Billheimer, J. T.; Germain, S. J.; Hausner, E. A.; Meunier, P. C.; Munzer, D. A.; Stoletenborg, J. K.; Gillies, P. J.; Burcham, D. L.; Huang, S.-M.; Klaczkiewicz, J. D.; Ko, S. S.; Wexler, R. R. ACAT inhibitors derived from hetero-Diels-Alder cycloadducts of thioaldehydes. Bioorg. Med. Chem. 1996, 4, 1493-1513.
23. Warner, G. J.; Stoudt, G.; Bamberger, M.; Johnson, W. J.; Rothblat, G. H. Cell toxicity induced by inhibition of acyl-CoA: cholesterol acyltransferase and accumulation of unesterified cholesterol. J. Biol. Chem. 1995, 270, 5772-5778.
24. Meiner, V. L.; Cases, S.; Myers, H. M.; Sande, E. R.; Bellosta, S.; Schambelan, M.; Pitas, R. E.; McGuire, J.; Herz, J.; Farese, R. V. Disruption of the acyl-CoA:cholesterol acyltransferase gene in mice: Evidence suggesting multiple cholesterol esterification enzymes in mammals. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 14041-14046.
25. Reindel, J. F., Dominick, M. A., Krause, B. R. Comparative adrenotoxicity of a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor (PD 132301-2) in laboratory animals. Toxicol. Pathol. 1992, 20, 642.
26. 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. Modifications of fatty acid anilide ACAT inhibitors: Bioisosteric replacement of the amide bond. J. Med. Chem. 1993, 36, 1662-1668.
27. Kitazume, T.; Murata, K.; Ikeya, T. Synthesis of the optically pure monoethyl ester of (R)-(+)-2-fluoromalonic acid by use of immobilized lipase-MY for asymmetric hydrolysis. J. Fluorine Chem. 1986, 31, 143-150.