Heterocyclic ureas: Inhibitors of acyl-CoA:cholesterol O- acyltransferase as hypocholesterolemic agents

Journal of Medicinal Chemistry

Volumn 39, Issue 22, 1996, Pages 4382-4395

  White, Andrew D ^a   Creswell, Mark W ^a   Chucholowski, Alexander W ^a   Blankley, C John ^a   Wilson, Michael W ^a   Bousley, Richard F ^a   Essenburg, Arnold D ^a   Hamelehle, Katherine L ^a   Krause, Brian R ^a   Stanfield, Richard L ^a   Dominick, Mark A ^a   Neub, Martin ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHOLESTEROL; CHOLESTEROL ACYLTRANSFERASE INHIBITOR; HETEROCYCLIC COMPOUND; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HYPOCHOLESTEROLEMIC AGENT; ISOXAZOLE DERIVATIVE; TETRAZOLE DERIVATIVE; UREA DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CHOLESTEROL INTAKE; DOG; DRUG STRUCTURE; DRUG SYNTHESIS; HYPERCHOLESTEROLEMIA; MALE; NONHUMAN; RABBIT; RAT;

ANIMALS; ANTICHOLESTEREMIC AGENTS; CHOLESTEROL, HDL; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DISEASE MODELS, ANIMAL; DOGS; FEMALE; HYPERCHOLESTEROLEMIA; MALE; RATS; STEROL O-ACYLTRANSFERASE; TETRAZOLES; UREA;

EID: 10244252718     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960404v     Document Type: Article

References (32)

1. This work has been presented in part: (a) Tetrazole Ureas: A Potent Series of Acyl-CoA:cholesterol acyltransferase (ACAT) Inhibitors. 202nd National ACS Meeting, 1991; MEDI 107. (b) Heterocyclic Ureas- Potent inhibitors of Acyl-CoA:cholesterol acyltransferase (ACAT) Part 2. 203rd National ACS Meeting, 1992; MEDI 141. (c) Heterocyclic Ureas- Potent inhibitors of Acyl-CoA:cholesterol acyltransferase (ACAT) Part 3. 203rd National ACS Meeting, 1992; MEDI 142.
2. This work has been presented in part: (a) Tetrazole Ureas: A Potent Series of Acyl-CoA:cholesterol acyltransferase (ACAT) Inhibitors. 202nd National ACS Meeting, 1991; MEDI 107. (b) Heterocyclic Ureas- Potent inhibitors of Acyl-CoA:cholesterol acyltransferase (ACAT) Part 2. 203rd National ACS Meeting, 1992; MEDI 141. (c) Heterocyclic Ureas- Potent inhibitors of Acyl-CoA:cholesterol acyltransferase (ACAT) Part 3. 203rd National ACS Meeting, 1992; MEDI 142.
3. This work has been presented in part: (a) Tetrazole Ureas: A Potent Series of Acyl-CoA:cholesterol acyltransferase (ACAT) Inhibitors. 202nd National ACS Meeting, 1991; MEDI 107. (b) Heterocyclic Ureas- Potent inhibitors of Acyl-CoA:cholesterol acyltransferase (ACAT) Part 2. 203rd National ACS Meeting, 1992; MEDI 141. (c) Heterocyclic Ureas- Potent inhibitors of Acyl-CoA:cholesterol acyltransferase (ACAT) Part 3. 203rd National ACS Meeting, 1992; MEDI 142.
4. 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, 365-73.
5. 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.
6. 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, 1383-9.
7. 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.
8. 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: Barcelona, Spain, 1986; pp 423-38.
9. 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.
10. Carr, T. P.; Hamilton, R. L., Jr.; 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.
11. 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, Spain, 1986; p 409.
12. Roark, W. H.; Roth, B. D. ACAT inhibitors: preclinical profiles of clinical candidates. Exp. Opin. Invest. Drugs 1994, 3, 1143-52.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. Trivedi, B. K.; Stoeber, T. S.; Stanfield, R. L.; Essenburg, A. D.; Hamelehle, K. L.; Krause, B. R. Substituted N,N′-Diphenyl Ureas as Potent Inhibitors of Acyl-CoA:Cholesterol Acyltransferase (ACAT). Bioorg. Med. Chem. Lett. 1993, 3, 259-62.
21. Poonian, M. S.; Nowoswiat, E. F.; Blount, J. F.; Williams, T. H.; Pitcher, R. G.; Kramer, M. J. Synthesis of tetrazole ribonucleosides and their evaluation as antiviral agents. J. Med. Chem. 1976, 19 (2), 286-90.
22. Kress, T. J.; Costantino, S. M. A Convenient and General Synthesis of 2-Amino-1,3,4-Thiadiazoles. Dehydration of Acylthiosemicarbazides with Methanesulfonic Acid. J. Heterocycl. Chem. 1980, 17, 607-8.
23. Gehlen, H.; Zeiger, G. 2-Amino-1,3,4-oxadiazoles. XXI. Reaction of aldonic acid hydrazides and cyanogen bromide. J. Prakt. Chem 1968, 37 (5-6), 269-77.
24. Barascut, J.-L.; Claramunt, R.-M. Etude de la methylation de l'amino-s-triazole et identification spectroscopique des differents derives N-methyles. Bull. Chem. Soc. Fr. 1973, 1849-53.
25. Murray, R. E.; Zweifel, G. Preparation of Phenyl Cyanate and its Utilization for the Synthesis of α,β-Unsaturated Nitriles. Synthesis 1980, 150-1.
26. Iwai, I.; Nakamura, N. Studies on Acetylenic Compounds. XLIV. Synthesis of 3-Aminoisoxazoles and 3-Hydroxyisoxazoles (3-Isoxazolones). Chem. Pharm. Bull. 1966, 14, 1277-86.
27. Cockerill, A. F.; Deacon, A.; Harrison, R. G.; Osborne, D. J.; Prime, D. M.; Ross, W. J.; Todd, A.; Verge, J. P. An Improved Synthesis of 2-Amino-1,3-Oxazoles under Basic Catalysis. Synthesis 1976, 591-3.
28. Searcey, M.; Pye, P. L.; Lee, J. B. Improved syntheses of N-substituted nitroimidazoles. Synth. Commun. 1989, 19 (7-8), 1309-15.
29. Dodson, R. M.; King, L. C. The Reaction of Ketones with Halogens and Thiourea. J. Am. Chem. Soc. 1945, 67, 2242-3.
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. BioByte Corp., MedChem, v. 3.55.
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.