ATP-citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R*,5S*)-ω-substituted-3-carboxy-3,5- dihydroxyalkanoic acids and their γ-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo

Journal of Medicinal Chemistry

Volumn 41, Issue 19, 1998, Pages 3582-3595

  Gribble, Andrew D ^a   Ife, Robert J ^a   Shaw, Antony ^a   McNair, David ^a   Novelli, Christine E ^a   Bakewell, Susan ^a   Shah, Virendra P ^a   Dolle, Roland E ^a,b   Groot, Pieter H ^a   Pearce, Nigel ^a   Yates, John ^a   Tew, David ^a   Boyd, Helen ^a   Ashman, Stephen ^a   Eggleston, Drake S ^a   Curtis Haltiwanger, R ^a   Okafo, George ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

^b PHARMACOPEIA INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 (CARBOXYMETHYL) 5 [6 (2,4 DICHLOROPHENYL)HEXYL] 3 HYDROXYTETRAHYDROFURAN 2 ONE; 3 CARBOXY 3,5 DIHYDROXYALKANOIC ACID DERIVATIVE; ADENOSINE TRIPHOSPHATE CITRATE LYASE; ANTILIPEMIC AGENT; CHOLESTEROL; ENZYME INHIBITOR; FATTY ACID; GAMMA LACTONE DERIVATIVE; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CHOLESTEROL SYNTHESIS; CONTROLLED STUDY; DOG; DRUG STRUCTURE; DRUG SYNTHESIS; FATTY ACID SYNTHESIS; HEPATOMA CELL; HUMAN; HUMAN CELL; HYPOCHOLESTEROLEMIA; HYPOLIPEMIA; IN VITRO STUDY; IN VIVO STUDY; INHIBITION KINETICS; LIPOGENESIS; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT; THERMODYNAMICS;

ADMINISTRATION, ORAL; ANIMALS; ANTICHOLESTEREMIC AGENTS; ANTILIPEMIC AGENTS; ATP CITRATE (PRO-S)-LYASE; CELL LINE; CHOLESTEROL; DOGS; ENZYME INHIBITORS; FATTY ACIDS; FURANS; HUMANS; LIPIDS; LIPOPROTEINS, VLDL; PRODRUGS; RATS; RECOMBINANT PROTEINS; STRUCTURE-ACTIVITY RELATIONSHIP; TRIGLYCERIDES;

EID: 15644363825     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm980091z     Document Type: Article

References (38)

1. (a) Srere, P. A. The Enzymology of the Formation and Breakdown of Citrate. Adv. Enzymol. 1975, 43, 57-101.
2. (b) Houston, B.; Nimmo, H. G. Purification and Some Kinetic Properties of Rat Liver ATP-Citrate Lyase. Biochem. J. 1984, 224, 437-443.
3. (c) Plowman, K. M.; Cleland, W. W. Purification and Kinetic Studies of the Citrate Cleavage Enzyme. J. Biol. Chem. 1967, 242, 4239-4247.
4. (d) Walsh, C. Enzyme Reaction Mechanisms; W. H. Freeman and Co.: San Francisco, 1979; pp 766-768.
5. (a) Gribble, A. D.; Dolle, R. E.; Shaw, A.; McNair, D.; Novelli, R.; Novelli, C. E.; Slingsby, B. P.; Shah, V. P.; Tew, D.; Saxty, B. A.; Allen, M.; Groot, P. H.; Pearce, N.; Yates, J. ATP-Citrate Lyase as a Target for Hypolipidemic Intervention. Design and Synthesis of 2-Substituted Butanedioic Acids as Novel, Potent Inhibitors of the Enzyme. J. Med. Chem. 1996, 39, 3569-3584.
6. (b) Dolle, R. E.; Gribble, A.; Wilks, T.; Kruse, L. I.; Eggleston, D.; Saxty, B. A.; Wells, T. N. C.; Groot, P. H. E. Synthesis of Novel Thiol-Containing Citric Acid Analogues. Kinetic Evaluation of These and Other Potential Active-Site-Directed and Mechanism-Based Inhibitors of ATP-Citrate Lyase. J. Med. Chem. 1995, 38, 537-543.
7. (c) Dolle, R. E.; McNair, D.; Hughes, M. J.; Kruse, L. I.; Eggleston, D.; Saxty, B. A.; Wells, T. N. C.; Groot, P. H. E. ATP-Citrate Lyase as a Target for Hypolipidemic Intervention. Sulfoximine and 3-Hydroxy-β-lactam Containing Analogues of Citric Acid as Potential Tight-Binding Inhibitors. J. Med. Chem. 1992, 35, 4875-4884.
8. (d) Saxty, B. A.; Novelli, R.; Dolle, R. E.; Kruse, L. I.; Reid, D. G.; Camilleri, P.; Wells, T. N. C. Synthesis and Evaluation of (+)- and (-)-2,2-Difluorocitrate as Inhibitors of Rat-liver ATP-Citrate Lyase and Porcine-Heart Aconitase. Eur. J. Biochem. 1992, 202, 889-896.
9. (e) Dolle, R. E.; Novelli, R.; Saxty, B. A.; Wells, T. N. C.; Kruse, L. I.; Camilleri, P.; Eggleston, D. Preparation of (+)-(Erythro)- and (+)-(Threo)-2-Vinyl Citric Acids as Potential Mechanism-Based Inhibitors of ATP-Citrate Lyase. Tetrahedron Lett. 1991, 32, 4587-4590.
10. Curran, D. P. In Advances in Cycloaddition; Curran, D. P., Ed.; JAI Press: Greenwich, CT, 1988; Vol. 1, pp 129-189.
11. For typical reaction see (a) Kim, T. H.; Sachihiko, I. Total Synthesis of (±)-(E)-8β, 17-Epoxylabd-12-ene-15,16,-dial. J. Chem. Soc., Chem Commun. 1983, 730-1. For synthesis of the phosphorane, see: (b) Cameron, A. F.; Duncanson, F. D.; Freer, A. A. J. Chem. Soc., Perkin Trans. 2 1975, 1030-1036.
12. For typical reaction see (a) Kim, T. H.; Sachihiko, I. Total Synthesis of (±)-(E)-8β, 17-Epoxylabd-12-ene-15,16,-dial. J. Chem. Soc., Chem Commun. 1983, 730-1. For synthesis of the phosphorane, see: (b) Cameron, A. F.; Duncanson, F. D.; Freer, A. A. J. Chem. Soc., Perkin Trans. 2 1975, 1030-1036.
13. (a) Davis, F. A.; Chattopadhyay, S.; Towson, J. C.; Lal, S.; Reddy, T. Chemistry of Oxaziridines. 9. Synthesis of 2-Sulfonyl and 2-Sulfamyloxaziridines Using Potassium Peroxymonosulfate (Oxone). J. Org. Chem. 1988, 53, 2087-2089.
14. (b) Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M. Synthesis of α-Hydroxy Carbonyl Compounds (Acyloins): Direct Oxidation of Enolates Using 2-Sulfonyloxaziridines. J. Org. Chem. 1984, 49, 3241-3243.
15. Okafo, G. N.; Bintz, C.; Clarke, S. E.; Camilleri, P. J. Chem. Soc., Chem. Commun. 1992, 1189-1192.
16. (a) Lewis, Y. S. Isolation and Properties of Hydroxycitric Acid. Methods Enzymol. 1969, 13, 613-619.
17. (b) Stallings, W. C.; Blount, J. F.; Srere, P. A.; Glusker, J. P. Structural Studies of Hydroxycitrates and Their Relevance to Certain Enzymatic Mechanisms. Arch. Biochem. Biophys. 1969, 193, 431-448.
18. (a) Sullivan, A. C.; Singh, M.; Srere, P. A..; Glusker, J. P. Reactivity and Inhibitor Potential of Hydroxycitrate Isomers with Citrate Synthase, Citrate Lyase and ATP-Citrate Lyase. J. Biol. Chem. 1977, 252, 7583-7590.
19. (b) Cheema-Dhadli, S.; Halperin, M. L.; Leznoff, C. C. Inhibition of Enzymes Which Interact With Citrate by (-)-Hydroxycitrate and 1,2,3-Tricarboxybenzene. Eur J. Biochem. 1973, 38, 98-102.
20. (c) Sullivan. A. C.; Hamilton, J. G.; Miller, O. N.; Wheatley, V. R. Inhibition of Lipogenesis in Rat Liver by (-)-Hydroxycitrate. Arch. Biochem. Biophys. 1977, 150, 183-190.
21. (d) Rudney, H.; Sexton, R. C. Regulation of Cholesterol Biosynthesis. Annu. Rev. Nutr. 1986, 6, 245-272.
22. Guthrie, R. W.; Kierstead, R. W. Amino Citric Acid Derivatives. U.S. Patent 3, 960,933, 1976.
23. SB laboratories, unpublished results.
24. Our initial lactonization method utilised stirring 45 in ether at room temperature with silica gel which had been impregnated with concentrated sulfuric acid. This produced a ca. 4:1 mixture, respectively, of the 5 and 6 ring lactones. Conversion to their repective methyl esters with diazomethane allowed ready separation of the two by flash column chromatography. However, when subjected to acid hydrolysis (25% HCl/Δ) to regenerate the carboxylic acids, both esters gave solely the thermodynamically favored 5 ring lactone 77. Indeed, we noticed that interconversion of the 6 ring lactone to 77 even occurred in the solid form of the 4:1 mixture of the two over a period of several months.
25. 77 has also been found to be efficacious as an inhibitor of de novo synthesis of cholesterol and fatty acids in primary rat hepatocytes. G. Gibbons, University of Oxford, unpublished results.
26. Wells, T. N. C. ATP-Citrate Lyase From Rat Liver. Characterisation of the Citryl-Enzyme Complexes. Eur. J. Biochem. 1991, 199, 163-186.
27. Hanch, C.; Leo, A. Substituent Constants for Correlation Analysis in Chemistry and Biology; John Wiley and Sons: New York, 1979.
28. We were unable to evaluate the γ-lactone of 72 due to insufficient compound being available.
29. (a) Pearce, N. J.; Yates, J. W.; Berkhout, T. A.; Jackson, B.; Tew, D.; Boyd, H.; Camilleri, P.; Sweeney, P.; Grabble, A. D.; Shaw, A.; Groot, P. H. E. The Role of ATP Citrate-lyase in the Metabolic Regulation of Plasma Lipids. Hypolipidemic Effects of SB-204990, a Lactone Prodrug of the Potent ATP Citrate-lyase Inhibitor SB-201076. Biochem. J., in press.
30. (b) These data have been presented in a poster: Groot, P. H. E.; Pearce, N. J.; Gribble, A. D.; Shaw, A. N.; Tew, D. G.; Wiggins, D.; Gibbons, G. F. Hepatic ATP-Citrate Lyase as a Target for Hypolipidaemic Intervention., Xth International Symposium on Atherosclerosis, Montreal, October 1994.
31. (a) Sugihara, H.; Matsumoto, N.; Hamuro, Y.; Kawamatsu, Y. Oral Hypoglycemic Agents: 1-(2-Carboxyphenyl)pyrroles. Arzneim. Forsch. (Drug Res.) 1974, 24, 1560-1563.
32. (b) Bell, M. R.; Zalay, A. W.; Oesterlin, R.; Clemens, S. D.; Dumas, D. J. Experimental Antiulcer Drugs. 1. Indole-1-alkanamides and Pyrrole-1-alkanamides. J. Med. Chem. 1997, 20, 5537-540.
33. (c) Oesterlin, R.; Bell, M. R.; McGarry, R. H.; Hlavac, A. G. Experimental Antiulcer Drugs. 2. 2-Substituted 2,4,5,6-Tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamides. J. Med. Chem. 1997, 20, 11068-1071.
34. Heath-Brown, B.; Philpott, P. G. Studies in the Indole Series. Part III. The Japp-Klingemann Reaction. J. Chem. Soc. 1965, 7185-7193.
35. Fleming, I.; Woolias, M. A New Synthesis of Indoles Particularly Suitable for the Synthesis of Tryptamines and Tryptamine Itself. J. Chem. Soc., Perkin Trans. 1 1979, 829-837.
36. Walser, A.; Silverman G. A New Synthesis of Indoles. J. Heterocycl. Chem. 1973, 10, 883.
37. Barclay, B. M.; Campbell N. Dehydrogenation of Tetrahydrocarbazoles by Chloranil. J. Chem. Soc. 1945, 530-533.
38. Campbell, N.; McCall, E. B. The Preparation of Tetrahydrocarbazoles from 2-Chlorocyclohexanone. J. Chem. Soc. 1950, 2870-2874.