ATP-citrate lyase as a target for hypolipidemic intervention. Design and synthesis of 2-substituted butanedioic acids as novel, potent inhibitors of the enzyme

Journal of Medicinal Chemistry

Volumn 39, Issue 18, 1996, Pages 3569-3584

  Gribble, Andrew D ^a   Dolle, Roland E ^a,b   Shaw, Antony ^a   McNair, David ^a   Novelli, Riccardo ^a   Novelli, Christine E ^a   Slingsby, Brian P ^a   Shah, Virendra P ^a   Tew, David ^a   Saxty, Barbara A ^a,c   Allen, Mark ^a   Groot, Pieter H ^a   Pearce, Nigel ^a   Yates, John ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

^b PHARMACOPEIA INC   (United States)

^c UNIVERSITY OF EDINBURGH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

11 (2,4 DICHLOROPHENYL) 3 HYDROXY 3 CARBOXY 5 OXOUNDECANOIC ACID; 2 [[[6 (2,4 DICHLOROPHENYL)HEXYL]THIO]METHYL] 2 HYDROXYBUTANEDIOIC ACID; 2 [[[6 (2,4 DICHLOROPHENYL)HEXYL]THIO]METHYL]BUTANEDIOIC ACID; ADENOSINE TRIPHOSPHATE CITRATE LYASE; ANTILIPEMIC AGENT; COMPACTIN; ENZYME INHIBITOR; FIBRIC ACID DERIVATIVE; GEMFIBROZIL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MEVINOLIN; PRAVASTATIN; SUCCINIC ACID DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CELL STRAIN HEPG2; CHOLESTEROL SYNTHESIS; COMPETITIVE INHIBITION; DRUG BINDING; DRUG DESIGN; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVE SITE; ENZYME INHIBITION; ENZYME KINETICS; FATTY ACID SYNTHESIS; NONHUMAN; NUCLEAR MAGNETIC RESONANCE;

ANIMALS; ANTILIPEMIC AGENTS; ATP CITRATE (PRO-S)-LYASE; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; KINETICS; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR CELLS, CULTURED;

EID: 9544254829     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960167w     Document Type: Article

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41. Although by no means a comprehensive list, see for example references 23a-c and (a) Roth, B. D.; Ortwine, D. F.; Hoefle, M. L.; Stratton, C. D.; Sliskovic, D. R.; Wilson, M. W.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 1. trans-6-(2-Pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a Novel Series of HMG-CoA Reductase Inhibitors. 1. Effects of Structural Modifications at the 2- and 5-Positions of the Pyrrole Nucleus. J. Med. Chem. 1990, 33, 21-31. (b) Sliskovic, D. R.; Roth, B. D.; Wilson, M. W.; Hoefle, M. L.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 2. 1,3,5-Trisubstituted [2-(Tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles. J. Med. Chem. 1990, 33, 31-38. (c) Roth, B. D.; Blankley, C. J.;Chucholowski, A. W.; Ferguson, E.;Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson, M. W. Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-l-yl)ethy]]-2H-pyran-2-one Inhibitors of HMG-CoA Reductase. 2. Effects of Introducing Substituents at Positions Three and Four of the Pyrrole Nucleus. J. Med. Chem. 1991, 34, 357-366. (d) Sit, S. Y.; Parker, R. A.; Motoc, I.; Han, W.; Balasubramanian, N.; Catt, J. D.; Brown, P. J.; Harte, W. E.; Thompson, M. D.; Wright, J. J. Synthesis, Biological Profile, and Quantitative Structure-Activity Relationship of a Series of Novel 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors. J. Med. Chem. 1990, 33, 2982-2999. (e) Jendralla, H.; Baader, E.; Bartmann, W.; Beck, G.; Bergmann, A.; Granzer, E.; Kerekjarto, B. v.; Kesseler, K.; Krause, R.; Schubert, W.; Wess, G. Synthesis and Biological Activity of New HMG-CoA Reductase Inhibitors. 2. Derivatives of 7-(1H-Pyrrol-3-yl)-substituted-3,5-dihydroxy hept-6(E)-enoic(-heptanoic) Acids. J. Med. Chem. 1990, 33, 61-70. (f) Stokker, G. E.; Alberts, A. W.; Gilfillan, J. L.; Huff, J. W.; Smith, R. L. 3-Hydroxy-3-methyl-glutaryl-coenzyme A Reductase Inhibitors. 5. 6-(Fluoren-9-yl) and 6-(Fluoren-9-ylidenyl)-3,5-dihydroxyhexanoic Acids and Their Lactone Derivatives. J. Med. Chem. 1986, 29, 852-855. (g) Prugh, J. D.; Alberts, A. W.; Deana, A. A.; Gilfillian, J. L.; Huff, J. W.; Smith, R. L.; Wiggins, J. W. 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 6. trans-6-[2-(Substituted-l-naphthyl)ethyl(or ethenyl)]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones. J. Med. Chem. 1990, 33, 758-765.
42. Although by no means a comprehensive list, see for example references 23a-c and (a) Roth, B. D.; Ortwine, D. F.; Hoefle, M. L.; Stratton, C. D.; Sliskovic, D. R.; Wilson, M. W.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 1. trans-6-(2-Pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a Novel Series of HMG-CoA Reductase Inhibitors. 1. Effects of Structural Modifications at the 2- and 5-Positions of the Pyrrole Nucleus. J. Med. Chem. 1990, 33, 21-31. (b) Sliskovic, D. R.; Roth, B. D.; Wilson, M. W.; Hoefle, M. L.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 2. 1,3,5-Trisubstituted [2-(Tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles. J. Med. Chem. 1990, 33, 31-38. (c) Roth, B. D.; Blankley, C. J.;Chucholowski, A. W.; Ferguson, E.;Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson, M. W. Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-l-yl)ethy]]-2H-pyran-2-one Inhibitors of HMG-CoA Reductase. 2. Effects of Introducing Substituents at Positions Three and Four of the Pyrrole Nucleus. J. Med. Chem. 1991, 34, 357-366. (d) Sit, S. Y.; Parker, R. A.; Motoc, I.; Han, W.; Balasubramanian, N.; Catt, J. D.; Brown, P. J.; Harte, W. E.; Thompson, M. D.; Wright, J. J. Synthesis, Biological Profile, and Quantitative Structure-Activity Relationship of a Series of Novel 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors. J. Med. Chem. 1990, 33, 2982-2999. (e) Jendralla, H.; Baader, E.; Bartmann, W.; Beck, G.; Bergmann, A.; Granzer, E.; Kerekjarto, B. v.; Kesseler, K.; Krause, R.; Schubert, W.; Wess, G. Synthesis and Biological Activity of New HMG-CoA Reductase Inhibitors. 2. Derivatives of 7-(1H-Pyrrol-3-yl)-substituted-3,5-dihydroxy hept-6(E)-enoic(-heptanoic) Acids. J. Med. Chem. 1990, 33, 61-70. (f) Stokker, G. E.; Alberts, A. W.; Gilfillan, J. L.; Huff, J. W.; Smith, R. L. 3-Hydroxy-3-methyl-glutaryl-coenzyme A Reductase Inhibitors. 5. 6-(Fluoren-9-yl) and 6-(Fluoren-9-ylidenyl)-3,5-dihydroxyhexanoic Acids and Their Lactone Derivatives. J. Med. Chem. 1986, 29, 852-855. (g) Prugh, J. D.; Alberts, A. W.; Deana, A. A.; Gilfillian, J. L.; Huff, J. W.; Smith, R. L.; Wiggins, J. W. 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 6. trans-6-[2-(Substituted-l-naphthyl)ethyl(or ethenyl)]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones. J. Med. Chem. 1990, 33, 758-765.
43. Although by no means a comprehensive list, see for example references 23a-c and (a) Roth, B. D.; Ortwine, D. F.; Hoefle, M. L.; Stratton, C. D.; Sliskovic, D. R.; Wilson, M. W.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 1. trans-6-(2-Pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a Novel Series of HMG-CoA Reductase Inhibitors. 1. Effects of Structural Modifications at the 2- and 5-Positions of the Pyrrole Nucleus. J. Med. Chem. 1990, 33, 21-31. (b) Sliskovic, D. R.; Roth, B. D.; Wilson, M. W.; Hoefle, M. L.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 2. 1,3,5-Trisubstituted [2-(Tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles. J. Med. Chem. 1990, 33, 31-38. (c) Roth, B. D.; Blankley, C. J.;Chucholowski, A. W.; Ferguson, E.;Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson, M. W. Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-l-yl)ethy]]-2H-pyran-2-one Inhibitors of HMG-CoA Reductase. 2. Effects of Introducing Substituents at Positions Three and Four of the Pyrrole Nucleus. J. Med. Chem. 1991, 34, 357-366. (d) Sit, S. Y.; Parker, R. A.; Motoc, I.; Han, W.; Balasubramanian, N.; Catt, J. D.; Brown, P. J.; Harte, W. E.; Thompson, M. D.; Wright, J. J. Synthesis, Biological Profile, and Quantitative Structure-Activity Relationship of a Series of Novel 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors. J. Med. Chem. 1990, 33, 2982-2999. (e) Jendralla, H.; Baader, E.; Bartmann, W.; Beck, G.; Bergmann, A.; Granzer, E.; Kerekjarto, B. v.; Kesseler, K.; Krause, R.; Schubert, W.; Wess, G. Synthesis and Biological Activity of New HMG-CoA Reductase Inhibitors. 2. Derivatives of 7-(1H-Pyrrol-3-yl)-substituted-3,5-dihydroxy hept-6(E)-enoic(-heptanoic) Acids. J. Med. Chem. 1990, 33, 61-70. (f) Stokker, G. E.; Alberts, A. W.; Gilfillan, J. L.; Huff, J. W.; Smith, R. L. 3-Hydroxy-3-methyl-glutaryl-coenzyme A Reductase Inhibitors. 5. 6-(Fluoren-9-yl) and 6-(Fluoren-9-ylidenyl)-3,5-dihydroxyhexanoic Acids and Their Lactone Derivatives. J. Med. Chem. 1986, 29, 852-855. (g) Prugh, J. D.; Alberts, A. W.; Deana, A. A.; Gilfillian, J. L.; Huff, J. W.; Smith, R. L.; Wiggins, J. W. 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 6. trans-6-[2-(Substituted-l-naphthyl)ethyl(or ethenyl)]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones. J. Med. Chem. 1990, 33, 758-765.
44. Although by no means a comprehensive list, see for example references 23a-c and (a) Roth, B. D.; Ortwine, D. F.; Hoefle, M. L.; Stratton, C. D.; Sliskovic, D. R.; Wilson, M. W.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 1. trans-6-(2-Pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a Novel Series of HMG-CoA Reductase Inhibitors. 1. Effects of Structural Modifications at the 2- and 5-Positions of the Pyrrole Nucleus. J. Med. Chem. 1990, 33, 21-31. (b) Sliskovic, D. R.; Roth, B. D.; Wilson, M. W.; Hoefle, M. L.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 2. 1,3,5-Trisubstituted [2-(Tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles. J. Med. Chem. 1990, 33, 31-38. (c) Roth, B. D.; Blankley, C. J.;Chucholowski, A. W.; Ferguson, E.;Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson, M. W. Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-l-yl)ethy]]-2H-pyran-2-one Inhibitors of HMG-CoA Reductase. 2. Effects of Introducing Substituents at Positions Three and Four of the Pyrrole Nucleus. J. Med. Chem. 1991, 34, 357-366. (d) Sit, S. Y.; Parker, R. A.; Motoc, I.; Han, W.; Balasubramanian, N.; Catt, J. D.; Brown, P. J.; Harte, W. E.; Thompson, M. D.; Wright, J. J. Synthesis, Biological Profile, and Quantitative Structure-Activity Relationship of a Series of Novel 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors. J. Med. Chem. 1990, 33, 2982-2999. (e) Jendralla, H.; Baader, E.; Bartmann, W.; Beck, G.; Bergmann, A.; Granzer, E.; Kerekjarto, B. v.; Kesseler, K.; Krause, R.; Schubert, W.; Wess, G. Synthesis and Biological Activity of New HMG-CoA Reductase Inhibitors. 2. Derivatives of 7-(1H-Pyrrol-3-yl)-substituted-3,5-dihydroxy hept-6(E)-enoic(-heptanoic) Acids. J. Med. Chem. 1990, 33, 61-70. (f) Stokker, G. E.; Alberts, A. W.; Gilfillan, J. L.; Huff, J. W.; Smith, R. L. 3-Hydroxy-3-methyl-glutaryl-coenzyme A Reductase Inhibitors. 5. 6-(Fluoren-9-yl) and 6-(Fluoren-9-ylidenyl)-3,5-dihydroxyhexanoic Acids and Their Lactone Derivatives. J. Med. Chem. 1986, 29, 852-855. (g) Prugh, J. D.; Alberts, A. W.; Deana, A. A.; Gilfillian, J. L.; Huff, J. W.; Smith, R. L.; Wiggins, J. W. 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 6. trans-6-[2-(Substituted-l-naphthyl)ethyl(or ethenyl)]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones. J. Med. Chem. 1990, 33, 758-765.
45. Although by no means a comprehensive list, see for example references 23a-c and (a) Roth, B. D.; Ortwine, D. F.; Hoefle, M. L.; Stratton, C. D.; Sliskovic, D. R.; Wilson, M. W.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 1. trans-6-(2-Pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a Novel Series of HMG-CoA Reductase Inhibitors. 1. Effects of Structural Modifications at the 2- and 5-Positions of the Pyrrole Nucleus. J. Med. Chem. 1990, 33, 21-31. (b) Sliskovic, D. R.; Roth, B. D.; Wilson, M. W.; Hoefle, M. L.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 2. 1,3,5-Trisubstituted [2-(Tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles. J. Med. Chem. 1990, 33, 31-38. (c) Roth, B. D.; Blankley, C. J.;Chucholowski, A. W.; Ferguson, E.;Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson, M. W. Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-l-yl)ethy]]-2H-pyran-2-one Inhibitors of HMG-CoA Reductase. 2. Effects of Introducing Substituents at Positions Three and Four of the Pyrrole Nucleus. J. Med. Chem. 1991, 34, 357-366. (d) Sit, S. Y.; Parker, R. A.; Motoc, I.; Han, W.; Balasubramanian, N.; Catt, J. D.; Brown, P. J.; Harte, W. E.; Thompson, M. D.; Wright, J. J. Synthesis, Biological Profile, and Quantitative Structure-Activity Relationship of a Series of Novel 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors. J. Med. Chem. 1990, 33, 2982-2999. (e) Jendralla, H.; Baader, E.; Bartmann, W.; Beck, G.; Bergmann, A.; Granzer, E.; Kerekjarto, B. v.; Kesseler, K.; Krause, R.; Schubert, W.; Wess, G. Synthesis and Biological Activity of New HMG-CoA Reductase Inhibitors. 2. Derivatives of 7-(1H-Pyrrol-3-yl)-substituted-3,5-dihydroxy hept-6(E)-enoic(-heptanoic) Acids. J. Med. Chem. 1990, 33, 61-70. (f) Stokker, G. E.; Alberts, A. W.; Gilfillan, J. L.; Huff, J. W.; Smith, R. L. 3-Hydroxy-3-methyl-glutaryl-coenzyme A Reductase Inhibitors. 5. 6-(Fluoren-9-yl) and 6-(Fluoren-9-ylidenyl)-3,5-dihydroxyhexanoic Acids and Their Lactone Derivatives. J. Med. Chem. 1986, 29, 852-855. (g) Prugh, J. D.; Alberts, A. W.; Deana, A. A.; Gilfillian, J. L.; Huff, J. W.; Smith, R. L.; Wiggins, J. W. 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 6. trans-6-[2-(Substituted-l-naphthyl)ethyl(or ethenyl)]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones. J. Med. Chem. 1990, 33, 758-765.
46. Although by no means a comprehensive list, see for example references 23a-c and (a) Roth, B. D.; Ortwine, D. F.; Hoefle, M. L.; Stratton, C. D.; Sliskovic, D. R.; Wilson, M. W.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 1. trans-6-(2-Pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a Novel Series of HMG-CoA Reductase Inhibitors. 1. Effects of Structural Modifications at the 2- and 5-Positions of the Pyrrole Nucleus. J. Med. Chem. 1990, 33, 21-31. (b) Sliskovic, D. R.; Roth, B. D.; Wilson, M. W.; Hoefle, M. L.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 2. 1,3,5-Trisubstituted [2-(Tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles. J. Med. Chem. 1990, 33, 31-38. (c) Roth, B. D.; Blankley, C. J.;Chucholowski, A. W.; Ferguson, E.;Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson, M. W. Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-l-yl)ethy]]-2H-pyran-2-one Inhibitors of HMG-CoA Reductase. 2. Effects of Introducing Substituents at Positions Three and Four of the Pyrrole Nucleus. J. Med. Chem. 1991, 34, 357-366. (d) Sit, S. Y.; Parker, R. A.; Motoc, I.; Han, W.; Balasubramanian, N.; Catt, J. D.; Brown, P. J.; Harte, W. E.; Thompson, M. D.; Wright, J. J. Synthesis, Biological Profile, and Quantitative Structure-Activity Relationship of a Series of Novel 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors. J. Med. Chem. 1990, 33, 2982-2999. (e) Jendralla, H.; Baader, E.; Bartmann, W.; Beck, G.; Bergmann, A.; Granzer, E.; Kerekjarto, B. v.; Kesseler, K.; Krause, R.; Schubert, W.; Wess, G. Synthesis and Biological Activity of New HMG-CoA Reductase Inhibitors. 2. Derivatives of 7-(1H-Pyrrol-3-yl)-substituted-3,5-dihydroxy hept-6(E)-enoic(-heptanoic) Acids. J. Med. Chem. 1990, 33, 61-70. (f) Stokker, G. E.; Alberts, A. W.; Gilfillan, J. L.; Huff, J. W.; Smith, R. L. 3-Hydroxy-3-methyl-glutaryl-coenzyme A Reductase Inhibitors. 5. 6-(Fluoren-9-yl) and 6-(Fluoren-9-ylidenyl)-3,5-dihydroxyhexanoic Acids and Their Lactone Derivatives. J. Med. Chem. 1986, 29, 852-855. (g) Prugh, J. D.; Alberts, A. W.; Deana, A. A.; Gilfillian, J. L.; Huff, J. W.; Smith, R. L.; Wiggins, J. W. 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 6. trans-6-[2-(Substituted-l-naphthyl)ethyl(or ethenyl)]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones. J. Med. Chem. 1990, 33, 758-765.
47. Although by no means a comprehensive list, see for example references 23a-c and (a) Roth, B. D.; Ortwine, D. F.; Hoefle, M. L.; Stratton, C. D.; Sliskovic, D. R.; Wilson, M. W.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 1. trans-6-(2-Pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a Novel Series of HMG-CoA Reductase Inhibitors. 1. Effects of Structural Modifications at the 2- and 5-Positions of the Pyrrole Nucleus. J. Med. Chem. 1990, 33, 21-31. (b) Sliskovic, D. R.; Roth, B. D.; Wilson, M. W.; Hoefle, M. L.; Newton, R. S. Inhibitors of Cholesterol Biosynthesis. 2. 1,3,5-Trisubstituted [2-(Tetrahydro-4-hydroxy-2-oxopyran-6-yl)ethyl]pyrazoles. J. Med. Chem. 1990, 33, 31-38. (c) Roth, B. D.; Blankley, C. J.;Chucholowski, A. W.; Ferguson, E.;Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson, M. W. Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-l-yl)ethy]]-2H-pyran-2-one Inhibitors of HMG-CoA Reductase. 2. Effects of Introducing Substituents at Positions Three and Four of the Pyrrole Nucleus. J. Med. Chem. 1991, 34, 357-366. (d) Sit, S. Y.; Parker, R. A.; Motoc, I.; Han, W.; Balasubramanian, N.; Catt, J. D.; Brown, P. J.; Harte, W. E.; Thompson, M. D.; Wright, J. J. Synthesis, Biological Profile, and Quantitative Structure-Activity Relationship of a Series of Novel 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors. J. Med. Chem. 1990, 33, 2982-2999. (e) Jendralla, H.; Baader, E.; Bartmann, W.; Beck, G.; Bergmann, A.; Granzer, E.; Kerekjarto, B. v.; Kesseler, K.; Krause, R.; Schubert, W.; Wess, G. Synthesis and Biological Activity of New HMG-CoA Reductase Inhibitors. 2. Derivatives of 7-(1H-Pyrrol-3-yl)-substituted-3,5-dihydroxy hept-6(E)-enoic(-heptanoic) Acids. J. Med. Chem. 1990, 33, 61-70. (f) Stokker, G. E.; Alberts, A. W.; Gilfillan, J. L.; Huff, J. W.; Smith, R. L. 3-Hydroxy-3-methyl-glutaryl-coenzyme A Reductase Inhibitors. 5. 6-(Fluoren-9-yl) and 6-(Fluoren-9-ylidenyl)-3,5-dihydroxyhexanoic Acids and Their Lactone Derivatives. J. Med. Chem. 1986, 29, 852-855. (g) Prugh, J. D.; Alberts, A. W.; Deana, A. A.; Gilfillian, J. L.; Huff, J. W.; Smith, R. L.; Wiggins, J. W. 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 6. trans-6-[2-(Substituted-l-naphthyl)ethyl(or ethenyl)]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones. J. Med. Chem. 1990, 33, 758-765.
48. (a) Stokker, G. E.; Hoffman, W. F.; Alberts, A. W.; Cragoe, E. J., Jr.; Deana, A. A.; Gilfillan, J. L.; Huff, J. W.; Novello, F. C.; Prugh, J. D.; Smith, R. L.; Willard, A. K. 3-Hydroxy-3-methyl-glutaryl-coenzyme A Reductase Inhibitors. 1. Structural Modification of 5-Substituted 3,5-Dihydroxypentanoic Acids and Their Lactone Derivatives. J. Med. Chem. 1985, 28, 347-358.
49. (b) Hoffman, W. F.; Alberts, A. W.; Cragoe, E. J., Jr.; Deana, A. A.; Evans, B. E.; Gilfillan, J. L.; Gould, N. P.; Huff, J. W.; Novello, F. C.; Prugh, J. D.; Rittle, K. E.; Smith, R. L.; Stokker, G. E.; Willard, A. K. 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 2. Structural Modification of 7-(Substituted aryl)-3,5-dihydroxy-6-heptenoic Acids and Their Lactone Derivatives. J. Med. Chem. 1986, 29, 159-169.
50. (c) Stokker, G. E.; Alberts, A. W.; Anderson, P. S.; Cragoe, E. J., Jr.; Deana, A. A.; Gilfillan, J. L.; Hirshfield, J.; Holtz, W. J.; Hoffman, W. F.; Huff, J. W.; Lee, T. J.; Novello, F. C.; Prugh, J. D.; Rooney, C. S.; Smith, R. L.; Willard, A. K. 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 3. 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors. 2. Structural Modification of 7-(3,5-Disubstituted [1,1′-biphenyl]-2-yl)-3,5-dihydroxy-6-heptenoic Acids and Their Lactone Derivatives. J. Med. Chem. 1986, 29, 170-181.
51. Beach, R. L.; Aogaichi, T.; Plaut, G. W. E. Identification of D-threo-α-Methylisocitrate as Stereochemically Specific Substrate for Bovine Heart Aconitase and Inhibitor of TNP-linked Isocitrate Dehydrogenase. J. Biol. Chem. 1977, 252, 2702-2709.
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55. 2+-citrate complex has been well-characterized in solution by NMR spectroscopy (Lowenstein, A.; Roberts, J. D. J. Am. Chem. Soc. 1960, 82, 2705) and in the solid-state by X-ray diffraction of the decahydrate form (Johnson, C. K. Acta Crystallogr. 1965, 18, 1004).
56. These data are only available against the recombinant human enzyme.
57. In a related series of compounds, to be reported in a subsequent paper, a 2-Ph,4-Cl substitution pattern did indeed give a significant improvement in activity over 2-Ph alone.
58. Garcinia cambogia was obtained from Joseph Flach & Sons Ltd., 140 Falkland Rd., London N8 ONP.
59. Trost, B. M.; Kunz, R. A. New Synthetic Reactions. A Convenient Approach to Methyl 3-oxo-4-pentenoate. J. Org. Chem. 1974, 39, 2648-2650.
60. (a) Wraight, C.; Day, A.; Hoogenraad, N.; Scopes, R. A Two-Step Purification of ATP-Citrate Lyase from Rat Liver and Its Use in a Fluorometric Assay for N-Acetylglutamate Synthetase. Anal. Biochem. 1985, 144, 604-609.
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