The squalestatins: Inhibitors of squalene synthase. Enzyme inhibitory activities and in vivo evaluation of C3-modified analogues

Journal of Medicinal Chemistry

Volumn 39, Issue 7, 1996, Pages 1413-1422

  Procopiou, Panayiotis A ^a   Cox, Brian ^a   Kirk, Barrie E ^a   Lester, Michael G ^a   McCarthy, Alun D ^a   Sareen, Meenu ^a   Sharratt, Peter J ^a   Snowden, Michael A ^a   Spooner, Stephen J ^a   Watson, Nigel S ^a   Widdowson, Julia ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

1 [4 (ACETYLOXY) 5 METHYL 3 METHYLENE 6 PHENYLHEXYL] 3 (HYDROXYMETHYL) 4,6,7 TRIHYDROXY 2,8 DIOXABICYCLO[3.2.1]OCTANE 4,5 DICARBOXYLIC ACID 6 (4,6 DIMETHYL 2 OCTENOATE); ANTILIPEMIC AGENT; SQUALENE SYNTHASE INHIBITOR; SQUALESTATIN DERIVATIVE; SQUALESTATIN H1; SQUALESTATIN S1; UNCLASSIFIED DRUG; ZARAGOZIC ACID A;

ANIMAL EXPERIMENT; ARTICLE; CHOLESTEROL BLOOD LEVEL; DRUG CONFORMATION; DRUG EFFECT; DRUG SYNTHESIS; ENZYME INHIBITION; FEMALE; HYPERLIPIDEMIA; INTRAVENOUS DRUG ADMINISTRATION; LIVER MICROSOME; MALE; MARMOSET; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTICHOLESTEREMIC AGENTS; BICYCLO COMPOUNDS, HETEROCYCLIC; CALLITHRIX; CHOLESTEROL; ENZYME INHIBITORS; ESTERS; FARNESYL-DIPHOSPHATE FARNESYLTRANSFERASE; MICROSOMES, LIVER; MOLECULAR STRUCTURE; RATS; TRICARBOXYLIC ACIDS;

EID: 13344259982     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm950893j     Document Type: Article

References (30)

1. Poulter, C. D.; Rilling, H. C. In Biosynthesis of Isoprenoid Compounds; Porter, J. W , Spurgeon, S. L., Eds.; Wiley: New York, 1981; Vol. 1, Chapter 1.
2. Dawson, M. J.; Farthing, J. E.; Marshall, P. S.; Middleton, R. F.; O'Neill, M, J.; Shuttleworth, A.; Stylli, C.; Tait, R. M.; Taylor, P M.; Wildman, G.; Buss, A. D.; Langley, D.; Hayes, M. V. The Squalestatins, Novel Inhibitors of Squalene Synthase Produced by a Species of Phoma. I. Taxonomy, Fermentation, Isolation, Physico-Chemical Properties and Biological Activity. J. Antibiot. 1992, 45, 639-647.
3. Blows, W. M.; Foster, G.; Lane, S. J.; Noble, D.; Piercey, J. E.; Sidebottom, P. J.; Webb, G. The Squalestatins: Novel Inhibitors of Squalene Synthase Produced by a Species of Phoma. V. Minor Metabolites. J. Antibiot. 1994, 47, 740-754.
4. Sidebottom, P. J.; Highcock, R. M.; Lane, S. J.; Procopiou, P. A.; Watson, N. S. The Squalestatins, Novel Inhibitors of Squalene Synthase Produced by a Species of Phoma II. Structure Elucidation. J. Antibiot. 1992, 45, 648-658.
5. Baxter, A.; Fitzgerald, B. J.; Hutson, J. L.; McCarthy, A. D.; Motteram, J. M.; Ross, B. C.; Sapra, M.; Snowden, M. A ; Watson, N. S.; Williams, R. J.; Wright, C. Squalestatin 1, a Potent Inhibitor of Squalene Synthase, Which Lowers Serum Cholesterol in. Vivo. J. Biol. Chem. 1992, 267, 11705-11708.
6. Procopiou, P A.; Bailey, E. J.; Bamford, M. J.; Craven, A. P.; Dymock, B. W.; Houston, J. G.; Hutson, J. L.; Kirk, B. E.; McCarthy, A. D.; Sareen, M.; Scicinski, J. J.; Sharratt, P. J.; Snowden, M. A.; Watson, N. S.; Williams, R. J. The Squalestatins: Novel Inhibitors of Squalene Synthase. Enzyme Inhibitory Activities and in Vivo Evaluation of C1-Modified Analogues. J. Med. Chem. 1994, 37, 3274-3281.
7. Bergstrom, J. D.; Kurtz, M. M.; Rew, D. J.; Amend, A. M.; Karkas, J. D.; Bostedor, R. G.; Bansal, V. S.; Dufresne, C.; VanMiddlesworth, F. L.; Hensens, O. D.; Liesch, J. M.; Zink, D. L.; Wilson, K. E.; Onishi, J.; Milligan, J. A.; Bills, G.; Kaplan, L.; Nallin Omstead, M.; Jenkins, R. G.; Huang, L.; Meinz, M. S.; Quinn, L.; Burg, R. W.; Kong, Y. L.; Mochales, S.; Mojena, M.; Martin, I.; Pelaez, P.; Diez, M. T.; Alberts, A. W. Zaragozic Acids: A Family of Fungal Metabolites that are Picomolar Competitive Inhibitors of Squalene Synthase. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 80-84.
8. Hensens, O. D.; Dufresne, C.; Liesch, J. M.; Zink, D. L.; Reamer, R. A.; VanMiddlesworth, F. The Zaragozic Acids: Structure Elucidation of a New Class of Squalene Synthase Inhibitors. Tetrahedron Lett. 1993, 34, 399-402.
9. Hasumi, K.; Tachikawa, K.; Sakai, K.; Marakawa, S.; Yoshikawa, N.; Kumazawa, S.; Endo, A. Competitive Inhibition of Squalene Synthase by Squalestatin 1. J. Antibiot. 1993, 46, 689-691.
10. Procopiou, P. A.; Bailey, E. J.; Hutson, J. L.; Kirk, B. E.; Sharratt, P. J.; Spooner, S. J.; Watson, N. S. The Squalestatins: Novel Inhibitors of Squalene Synthase. The Optimal C1 Chain-length Requirements. BioMed. Chem. Lett. 1993, 3, 2027-2532.
11. Watson, N. S.; Bell, R.; Chan, C.; Cox, B.; Hutson, J. L.; Keeling, S. E.; Kirk, B. E.; Procopiou, P. A.; Steeples, I. P.; Widdowson, J. The Squalestatins: Potent Inhibitors of Squalene Synthase. The Role of the Tricarboxylic Acid Moiety. BioMed. Chem. Lett. 1993, 3, 2541-2546.
12. Giblin, G. M. P.; Bell, R.; Hancock, A. P.; Hartley, C. D.; Inglis, G. G. A.; Payne, J. J.; Procopiou, P. A.; Shingler, A. H.; Smith, C.; Spooner, S. J. Semisynthetic Squalestatins: Squalene Synthase Inhibition and Antifungal Activity. The SAR of C6 and C7 Modifications. BioMed. Chem. Lett. 1993, 3, 2605-2610.
13. Lester, M. G.; Giblin, G. M. P.; Inglis, G. G. A.; Procopiou, P A.; Ross, B. C.; Watson, N. S. Structurally simplified Squalestatins: A Convenient Route to a 6,7-Unsubstituted Derivative. Tetrahedron Lett. 1993, 34, 4357-4360.
14. Chan. C.; Inglis, G. G. A.; Procopiou, P. A.; Ross, B. C.; Srikantha, A. R. P.; Watson, N. S. The Squalestatins: C-3 Decarboxylation Studies and Rearrangement to the 6,8-Dioxabicyclo[3.2.1]octane Ring System. Tetrahedron Lett. 1993, 34, 6143-6146.
15. Chan, C., Andreotti, D.; Dymock, B. W.; Keeling, S. E.; Procopiou, P. A.; Ross, B. C.; Sareen, M.; Sharratt, P. J.; Snowden, M. A.; Watson, N. S. The Squalestatins: Decarboxy and 4-Deosy Analogues as Potent Squalene Synthase Inhibitors. J. Med. Chem. 1996, 39, 207-216.
16. Sharratt, P. J.; Hutson, J. L.; Inglis, G. G. A.; Lester, M. G.; Procopiou, P. A.; Watson, N. S. Structurally Simplified Squalestatins: Monocyclic 1,3-Dioxane Analogues. BioMed. Chem. Lett. 1994, 4, 661-666.
17. Andreotti, D ; Procopiou, P. A.; Watson, N S. The Squalestatins: Cleavage of the Bicyclic Core via the Novel 2,8,9-Trioxabicyclo[3.3.1]nonane Ring System. Tetrahedron. Lett. 1994, 35, 1789-1792.
18. Procopiou, P. A.; Bailey, E. J.; Chan, C.; Inglis, G. G. A.; Lester, M. G.; Srikantha, A. R. P ; Sidebottom, P. J.; Watson, N. S. The Squalestatins: Cleavage of the Bicyclic Core via the Novel 6,8-dioxabicyclo[3.2.1]octane Ring System. J. Chem. Soc., Perkin Trans. 1 1995, 1341-1347.
19. Cox, B.; Hutson, J. L.; Keeling, S. E.; Kirk, B. E.; Srikantha, A. R. P.; Watson, N. S. The Squalestatins: Potent Inhibitors of Squalene Synthase, 3-hydroxymethyl Derivatives. BioMed. Chem. Lett. 1994, 4, 1931-1936.
20. Bamford, M. J.; Chan, C.; Craven, A. P.; Dymock, B. W.; Green, D.; Henson, R. A.; Kirk, B. E.; Lester M. G.; Procopiou, P. A.; Snowden, M. A.; Spooner, S. J.; Srikantha, A. R. P.; Watson, N. S.; Widdowson, J. A. The Squalestatins: Synthesis and Biological Activity of Some C3-Modified Analogues; Replacement of a Carboxylic Acid or Methyl Ester with an Isoelectronic Heterocyclic Functionality. J Med. Chem. 1995, 38, 3502-3513.
21. Lester, M. G.; Evans, G. L.; Henson, R. A.; Procopiou, P. A.; Sareen, M.; Snowden, M. A.; Spooner, S. J.; Srikantha, A. R. P.; Watson, N. S. The Squalestatins: Effects of Changes at the Allylic Centre in the C1 sidechain. BioMed. Chem. Lett. 1994, 4, 2683-2688.
22. Watson, N. S.; Procopiou, P. A. In Progress in Medicinal Chemistry; Ellis, G. P., Luscombe, D. K., Eds.; Elsevier: Amsterdam, 1996; Vol. 33, Chapter 7.
23. Kuo, C. H.; Plevyak, S. P.; Biftu, T.; Parsons, W. H.; Berger, G. D. The Synthesis of C3-Methyl, C3-Decarboxy-Zaragozic Acid A-A Potent Squalene Synthase Inhibitor. Tetrahedron Lett. 1993, 34, 6863-6866.
24. 4. Chem. Lett. 1979, 981-982.
25. Elsinger, F.; Schreiber, J.; Eschenmoser, A. Notiz uber die Selektivität der Spaltung von Carbonsäure-methylestern mit Lithiumjodid. (A Note on the Selective Cleavage of Methyl Esters of Carboxylic Acids with Lithium Iodide.) Helv. Chim. Acta 1960, 43, 113-118.
26. Compound 10 was unstable to storage, rearranging to a mixture of 3- and 4-MEM ethers.
27. Miller, A. E.; Bischoff, J. J. A Facile Conversion of Amino Acids to Guanidino Acids. Synthesis 1989, 777-779.
28. Tait, R. M. Development of a Radiometrie Spot-Wash Assay for Squalene Synthase. Anal. Biochem. 1992, 203, 310-316.
29. 3H]-label for S1 was introduced at C7 via reduction of a 7-keto derivative, and the label for 1b was introduced at the C3′ methylene via reduction of an active ester at C3.
30. Evans, G. L. unpublished results.