Inhibitors of acyl-coA:cholesterol O-acyltransferase. 2. Identification and structure-activity relationships of a novel series of N-alkyl-N- (heteroaryl-substituted benzyl)-N'-arylureas

Journal of Medicinal Chemistry

Volumn 41, Issue 13, 1998, Pages 2390-2410

  Tanaka, Akira ^a   Terasawa, Takeshi ^a   Hagihara, Hiroyuki ^a   Sakuma, Yuri ^a   Ishibe, Noriko ^a   Sawada, Masae ^a   Takasugi, Hisashi ^a   Tanaka, Hirokazu ^b  

^a ASTELLAS PHARMA INC   (Japan)

^b Med Chemistry Research Laboratories

Author keywords

[No Author keywords available]

Indexed keywords

3 (2,4 DIFLUOROPHENYL) 1 HEPTYL 1 (4 NEOPENTYLBENZYL)UREA; ACETYL LOW DENSITY LIPOPROTEIN; CHOLESTEROL ACYLTRANSFERASE INHIBITOR; CHOLESTEROL ESTER; DRUG VEHICLE; FR 182980; FR 186054; MACROGOL; N BENZYL N [3 (PYRAZOL 3 YL)BENZYL] N' [2,4 BIS(METHYLTHIO) 6 METHYLPYRIDIN 3 YL]UREA; UNCLASSIFIED DRUG;

ADRENAL GLAND; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; DOG; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG POTENCY; ENZYME INHIBITION; HYPERCHOLESTEROLEMIA; INTRAVENOUS DRUG ADMINISTRATION; MICROSOME; MOUSE; NONHUMAN; ORAL DRUG ADMINISTRATION; PERITONEUM MACROPHAGE; RABBIT; RAT; STRUCTURE ACTIVITY RELATION; TOXICITY TESTING;

ADMINISTRATION, ORAL; ADRENAL CORTEX; ANIMALS; ANTICHOLESTEREMIC AGENTS; CHOLESTEROL; CHOLESTEROL, DIETARY; DOGS; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; ENZYME INHIBITORS; INTESTINAL MUCOSA; INTESTINE, SMALL; MICROSOMES; NECROSIS; PYRAZOLES; RABBITS; RATS; STEROL O-ACYLTRANSFERASE; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 0032543617     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9800853     Document Type: Article

References (60)

1. A portion of this work was communicated in a preliminary form: Tanaka, A.; Terasawa, T.; Hagihara, H.; Kinoshita, T.; Sakuma, Y.; Ishibe, N.; Sawada, M.; Takasugi, H.; Tanaka, H. Synthesis, X-ray Crystal Structure, and Biological Activity of FR186054, a Novel, Potent, Orally Active Inhibitor of Acyl-CoA; Cholesterol O-Acyltransferase (ACAT) Bearing a Pyrazole Ring. Bioorg. Med. Chem. Lett. 1998, 8, 81-86.
2. Kannel, W. B.; Castelli, W. P.; Gordon, T.; McNamara, P. M. Serum Cholesterol, Lipoproteine, and the Risk of Coronary Heart Disease. The Framingham Study. Ann. Intern. Med. 1971, 74, 1-12.
3. (a) Martin, M. J.; Hulley, S. B.; Browner, W. S.; Kuller, L. H.; Wentworth, D. Serum Cholesterol, Blood Pressure, and Mortality: Implications from a Cohort of 361 662 Men. Lancet 1986, 2, 933-936.
4. (b) Badimon, J. J.; Fuster, V.; Chesebro, J. H.; Badimon, L. Coronary Atherosclerosis: A Multifactorial Disease. Circulation 1993, 87 (suppl. II), 3-16.
5. McCarthy, P. A. New Approaches to Atherosclerosis: An Overview. Med. Res. Rev. 1993, 13, 139-159.
6. For the role of ACAT, see: (a) Spector, A. A.; Mathur, S. N.; Kaduce, T. L. Role of Acylcoenzyme A:Cholesterol O-Acyltransferase in Cholesterol Metabolism. Prog. Lipid Res. 1979, 18, 31-53, (b) Suckling, K. E.; Stange, E. F. Role of Acyl-CoA:Cholesterol Acyltransferase in Cellular Cholesterol Metabolism. J. Lipid Res. 1985, 26, 647-671.
7. For the role of ACAT, see: (a) Spector, A. A.; Mathur, S. N.; Kaduce, T. L. Role of Acylcoenzyme A:Cholesterol O-Acyltransferase in Cholesterol Metabolism. Prog. Lipid Res. 1979, 18, 31-53, (b) Suckling, K. E.; Stange, E. F. Role of Acyl-CoA:Cholesterol Acyltransferase in Cellular Cholesterol Metabolism. J. Lipid Res. 1985, 26, 647-671.
8. (a) Krause, B. R.; Anderson, M.; Bisgaier, C. L.; Bocan, T.; Bousley, R.; DeHart, P.; Essenburg, A.; Hamelehle, K.; Homan, R.; Kieft, K.; McNally, W.; Stanfield, R.; Newton, R. S. In Vivo Evidence that the Lipid-regulating Activity of the ACAT Inhibitor CI-976 in Rats is Due to Inhibition of Both Intestinal and Liver ACAT. J. Lipid Res. 1993, 34, 279-294.
9. (b) Largis, E. E.; Wang, C. H.; DeVries, V. G.; Schaffer, S. A. CL 277, 082: A Novel Inhibitor of ACAT-Catalyzed Cholesterol Esterification and Cholesterol Absorption. J. Lipid Res. 1989, 30, 681-690.
10. Carr, T. P.; Rudel, L. L. Partial Inhibition of ACAT Decreases ApoB Secretion by the Liver of African Green Monkeys. Arteriosclerosis 1990, 10, 823a.
11. Carr, T. P.; Parks, J. S.; Rudel, L. L. Hepatic ACAT Activity in African Green Monkeys is Highly Correlated to Plasma LDL Cholesteryl Ester Enrichment and Coronary Atherosclerosis. Arterioscler. Thromb. 1992, 12, 1274-1283.
12. (e) Burrier, R. E.; Deren, S.; McGregor, D. G.; Hoos, L. M.; Smith, A. A.; Davis, H. R., Jr. Demonstration of a Direct Effect on Hepatic Acyl CoA: Cholesterol Acyl Transferase (ACAT) Activity by an Orally Administered Enzyme Inhibitor in the Hamster. Biochem. Pharmacol. 1994, 47, 1545-1551.
13. (a) Brown, M. S.; Goldstein, J. L. Lipoprotein Metabolism in the Macrophage: Implications for Cholesterol Deposition in Atherosclerosis. Annu. Rev. Biochem. 1983, 52, 223-261.
14. (b) Gillies, P. J.; Robinson, C. S.; Rathgeb, K. A. Regulation of ACAT Activity by a Cholesterol Substrate Pool During the Progression and Regression Phases of Atherosclerosis: Implications for Drug Discovery. Atherosclerosis 1990, 83, 177-185
15. . (8) Sliskovic, D. R.; White, A. D. Therapeutic Potential of ACAT Inhibitors as Lipid Lowering and Anti-Atherosclerotic Agents. Trends Pharmacol. Sci. 1991, 12, 194-199.
16. For recent reviews of ACAT inhibitors, see: (a) Picard, J. A. Patent Update: ACAT Inhibitors. Curr. Opin. Ther. Pat. 1993, 3, 151-160. (b) Matsuda, K. ACAT Inhibitors as Antiatherosclerotic Agents: Compounds and Mechanisms. Med. Res. Rev. 1994, 14, 271-305. Sliskovic, D. R.; Trivedi, B. K. ACAT Inhibitors: Potential Anti-atherosclerotic Agents. Curr. Med. Chem. 1994, 1, 204-225.
17. For recent reviews of ACAT inhibitors, see: (a) Picard, J. A. Patent Update: ACAT Inhibitors. Curr. Opin. Ther. Pat. 1993, 3, 151-160. (b) Matsuda, K. ACAT Inhibitors as Antiatherosclerotic Agents: Compounds and Mechanisms. Med. Res. Rev. 1994, 14, 271-305. Sliskovic, D. R.; Trivedi, B. K. ACAT Inhibitors: Potential Anti-atherosclerotic Agents. Curr. Med. Chem. 1994, 1, 204-225.
18. For recent reviews of ACAT inhibitors, see: (a) Picard, J. A. Patent Update: ACAT Inhibitors. Curr. Opin. Ther. Pat. 1993, 3, 151-160. (b) Matsuda, K. ACAT Inhibitors as Antiatherosclerotic Agents: Compounds and Mechanisms. Med. Res. Rev. 1994, 14, 271-305. Sliskovic, D. R.; Trivedi, B. K. ACAT Inhibitors: Potential Anti-atherosclerotic Agents. Curr. Med. Chem. 1994, 1, 204-225.
19. (a) DeVries, V. G.; Schaffer, S. A; Largis, E. E.; Dutia, M. D.; Wang, C.-H.; Bloom, J. D.; Katoca, A. S., Jr. Potential Antiatherosclerotic Agents. 5. An Acyl-CoA:Cholesterol O-Acyltransferase Inhibitor with Hypocholesterolemic Activity. J. Med. Chem. 1986, 29, 1131-1133.
20. (b) DeVries, V. G.; Bloom, J. D.; Dutia, M. D.; Katocs, A. S., Jr.; Largis, E. E. Potential Antiatherosclerotic Agents. 6. Hypocholesterolemic Trisubstituted Urea Analogues. J. Med. Chem. 1989, 32, 2318-2325.
21. (a) Largis, E. E.; Wang, C. H.; DeVries, V. G.; Schaffer, S. A. CL 277, 082: A Novel Inhibitor of ACAT-Catalyzed Cholesterol Esterification and Cholesterol Absorption, J. Lipid Res. 1989, 30,681-690.
22. (b) Burrier, R. E.; Deren, S.; McGregor, D. G.; Hoos, L. M.; Smith, A. A.; Davis, H. R., Jr. Demonstration of a Direct Effect on Hepatic Acyl CoA:Cholesterol Acyl Transferase (ACAT) Activity by an Orally Administered Enzyme Inhibitor in the Hamster. Biochem. Pharmacol. 1994, 47, 1545-1551.
23. 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, 189-194.
24. For recent results of clinical trials, see: (a) Roark, W. H.; Roth, B. D. ACAT Inhibitors: Preclinical Profiles of Clinical Candidates. Exp. Opin. Invest. Drugs 1994, 3, 1143-1152. (b) Lee, H. T.; Picard, J. A. Recent Developments in Hypocholesterolemic Agents. Exp. Opin. Ther. Pat. 1995, 5, 397-416 and references therein.
25. For recent results of clinical trials, see: (a) Roark, W. H.; Roth, B. D. ACAT Inhibitors: Preclinical Profiles of Clinical Candidates. Exp. Opin. Invest. Drugs 1994, 3, 1143-1152. (b) Lee, H. T.; Picard, J. A. Recent Developments in Hypocholesterolemic Agents. Exp. Opin. Ther. Pat. 1995, 5, 397-416 and references therein.
26. Tanaka, A.; Terasawa, T.; Hagihara, H.; Sakuma, Y.; Ishibe, N.; Sawada, M.; Takasugi, H.; Tanaka, H. Inhibitors of Acyl-CoA: Cholesterol O-Acyltransferase (ACAT). Part 1: Identification and Structure-Activity Relationships of a Novel Series of Substituted AT-Alkyl-N-biphenylylmethyl-N′-arylureas. Bioorg. Med. Chem. 1998, 6, 15-30.
27. (a) Siddiqui, M. A.; Snieckus, V. The Directed Metalation Connection to Aryl-Aryl Cross Coupling. Regiospecific Synthesis of Phenanthridines, Phenanthridinones and the Biphenyl Al-kaloid Ismine. Tetrahedron Lett. 1988, 29, 5463-5466 and references therein,
28. (b) Shieh, W.-C.; Carlson, J. A. A Simple Asymmetric Synthesis of 4-Arylphenylalanines via PalladiumCatalyzed Cross-Coupling Reaction of Arylboronic Acids with Tyrosine Triflate. J. Org. Chem. 1992, 57, 379-381.
29. Koch, K.-H.; Müllen, K. Synthesis of Tetraalkyl-Substituted Oligo(1,4-naphthylene)s and Cyclization to Soluble Oligo(peri-naphthylene)s. Chem. Ber. 1991, 124, 2091-2100.
30. Stille, J. K. The Palladium-Catalyzed Cross-Coupling Reactions of Organotin Reagents with Organic Electrophiles. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
31. Hansch, C.; Rockwell, S. D.; Jow, P. Y. C.; Leo, A; Steller, E. E. Substituent Constants for Correlation Analysis. J. Med. Chem. 1977, 20, 304-306.
32. The structures of 23a and 24a were confirmed by X-ray crystallographic analyses (data not shown).
33. Hüttel, R.; Wagner, H.; Jochum, P. Die Bromierung der Pyrazole. (Bromination of Pyrazole.) Liebigs Ann. Chem. 1955, 593, 179-200.
34. Carlsen, P. H. J.; Jørgensen, K. B. Synthesis of Unsymmetrically Substituted 4H-1,2,4-Triazoles. J. Heterocycl. Chem. 1994, 31, 805-807.
35. 33 The N-methyl protons of 2-isomer are downfield from the 1-isomer.
36. Ishikura, M.; Kamada, M.; Terashima, M. A Convenient Synthesis of 3-Arylpyridines by the Palladium Catalyzed Coupling Reaction of Diethyl(3-Pyridyl)Borane with Aryl Halides. Heterocycles 1984, 22, 265-268.
37. Heider, J. G.; Pickens, C. E.; Kelly, L. A. Role of Acyl CoA: Cholesterol Acyltransferase in Cholesterol Absorption and Its Inhibition by 57-118 in the Rabbit. J. Lipid Res. 1983, 24, 1127-1134.
38. Sakuma, Y.; Hagihara, H.; Ohne, K.; Nagayoshi, A.; Mutoh, S.; Ito, Y.; Notsu, Y.; Okuhara, M. Plasma Cholesterol Reducing Effect of FR129169, A Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, in the Rat. Jpn. J. Pharmacol. 1996, 70, 35-41.
39. Sliskovic, D. R.; Krause, B. R.; Picard, J. A.; Andersen, M.; Bousley, R. F.; Hamelehle, K. L.; Homan, R.; Julian, T. N.; Rashidbaigi, Z. A.; Stanfield, R. L. Inhibitors of Acyl-CoA: cholesterol O-Acyl Transferase (ACAT) as Hypocholesterolemic Agents. 6. The First Water-Soluble ACAT Inhibitor with Lipid-Regulating Activity. J. Med. Chem. 1994, 37, 560-562.
40. (a) Largis, E. E.; Katocs, A. S., Jr. Abstracts of Papers, 10th International Symposium on Drugs Affecting Lipid Metabolism, Houston, 1989, p 33.
41. (b) Wrenn, S. M., Jr.; Parks, J. S.; Immermann, F. W.; Rudel, L. L. ACAT Inhibitors CL 283,546 and CL 283,796 Reduce LDL Cholesterol without Affecting Cholesterol Absorption in African Green Monkeys. J. Lipid Res. 1995, 36, 1199-1210.
42. (a) 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.
43. (b) Inskeep, P. B.; Davis, K. M.; Reed, A. E. Pharmacokinetics of the Acyl Coenzyme A:Cholesterol Acyl Transferase Inhibitor CP-105,191 in Dogs-The Effect of Food and Sesame Oil on Systemic Exposure following Oral Dosing. J. Pharm. Sci. 1995, 84, 131-133.
44. (a) Chang, T. Y.; Chang, C. C. Y.; Cheng, D. Acyl-Coenzyme A:Cholesterol Acyltransferase. Annu. Rev. Biochem. 1997, 66, 613-638.
45. (b) Sturley, S. L. Molecular Aspects of Intracellular Sterol Esterification: the Acyl Coenzyme A:Cholesterol Acyltransferase Reaction. Curr. Opin. Lipidol. 1997, 8, 167-173 and references therein.
46. (a) 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 Acyl-CoA:Cholesterol Acyltransferase. Toxicol. Pathol. 1993, 21, 54-62.
47. (b) 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.
48. Dominick, M. A.; McGuire, E. J.; Reindel, J. F.; Bobrowski, W. F.; 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.
49. Reindel, J. F.; Dominick, M. A.; Bocan, T. M. A.; Gough, A. W.; McGuire, E. J. Toxicologie Effects of a Novel Acyl-CoA: Cholesterol Acyltransferase Inhibitor in Cynomolgus Monkeys. Toxicol. Pathol. 1994, 22, 510-518.
50. (e) Wolfgang, G. H. I.; MacDonald, J. R.; Vernetti, L. A.; Pegg, D. G.; Robertson, D. G. Biochemical Alterations in Guinea Pig Adrenal Cortex Following Administration of PD 132301-2, an Inhibitor of Acyl-CoA: Cholesterol Acyltransferase. Life Sci. 1995, 13, 1089-1093.
51. (a) Smith, C.; Ashton, M. J.; Bush, R. C.; Facchini, V.; Harris, N. V.; Hart, T. W.; Jordan, R.; McKenzie, R.; Riddell, D. RP 73163: A Bioavailable Alkylsulphinyl-Diphenylimidazole ACAT Inhibitor. Bioorg. Med. Chem. Lett. 1996, 6, 47-50.
52. (b) 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: Choies terol 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.
53. O'Brien, P. M.; Sliskovic, D. R.; Picard, J. A.; Lee, H. T.; Purchase, C. F., II; Roth, B. D.; White, A. D.; Anderson, M.; Mueller, S. B.; Bocan, T.; Bousley, R.; Hamelehle, K. L.; Homan, R.; Lee, P.; Krause, B. R.; Reindel, J. F.; Stanfield, R. L.; Turluck, D. Inhibitors of Acyl-CoA:Cholesterol O-Acyltransferase. Synthesis and Pharmacological Activity of (±)-2-Dodecylα-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5- acetamide and Structurally Related Tetrazole Amide Derivatives. J. Med. Chem. 1996, 39, 2354-2366.
54. Purchase, C. F., II; White, A. D.; Anderson, M. K.; Bocan, T. M. A.; Bousley, R. F.; Hamelehle, K. L.; Homan, R.; Krause, B. R.; Lee, P.; Mueller, S. B.; Speyer, C.; Stanfield, R. L.; Reindel, J. F. Tetrazole-substituted Ureas as Inhibitors of Acyl-CoA:Cholesterol O-Acyltransferase (ACAT). A Novel Preparation of Ureas from Weakly Nucleophilic Amines. Bioorg. Med. Chem. Lett. 1996, 6, 1753-1758.
55. (e) White, A. D.; Creswell, M. W.; Chucholowski, A. W.; Blankley, C. J.; Wilson, M. W.; Bousley, R. F.; Essenburg, A. D.; Hamelehle, K. L.; Krause, B. R.; Stanfield, R. L.; Dominick, M. A.; Neub, M. Heterocyclic Ureas: Inhibitors of Acyl-CoA: Cholesterol O-Acyltransferase as Hypocholesterolemic Agents. J. Med. Chem. 1996, 39, 4382-4395.
56. (f) Wilde, R. G.; Billheimer, J. T.; Germain, S. J.; Hausner, E. A.; Meunier, P. C.; Munzer, D. A.; Stoltenborg, 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.
57. Warner, G. J.; Stoudt, G.; Bamberger, M.; Johnson, W. J.; Rothblat, G. H. Cell Toxicity Induced by Inhibition of Acyl Coenzyme A:Cholesterol Acyltransferase and Accumulation of Unesterified Cholesterol. J. Biol. Chem. 1995, 270, 5772-5778.
58. 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, FR145237. Toxicol. Appl. Pharmacol. 1996, 140, 387-392.
59. White, A. D.; Purchase, C. F., II; Picard, J. A.; Anderson, M. K.; Mueller, S. B.; 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 O-Acyl Transferase with Hypocholesterolemic Activity in Several Species and Antiatherosclerotic Activity in the Rabbit. J. Med. Chem. 1996, 39, 3908-3919.
60. Butler, R. N. A Study of the Proton Nuclear Magnetic Resonance Spectra of Aryl and Mono- and Disubstituted N-Methylazoles. Can. J. Chem. 1973, 51, 2315-2322.