Quinuclidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase: Optimization from lipid profiles

Journal of Medicinal Chemistry

Volumn 42, Issue 7, 1999, Pages 1306-1311

  Brown, George R ^a   Hollinshead, David M ^a   Stokes, Elaine S E ^a   Clarke, David S ^a   Eakin, M Allan ^a   Foubister, Alan J ^a   Glossop, Steven C ^a   Griffiths, David ^a   Johnson, Michael C ^a   McTaggart, Fergus ^a   Mirrlees, Donald J ^a   Smith, Graham J ^a   Wood, Robin ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CHOLESTEROL; LANOSTEROL SYNTHASE; QUINUCLIDINE DERIVATIVE; SQUALENE SYNTHASE;

ANTIOXIDANT ACTIVITY; ARTICLE; CHOLESTEROL SYNTHESIS; ENZYME ACTIVITY; ENZYME INHIBITION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HYPOCHOLESTEROLEMIA; LIPID ANALYSIS;

ADMINISTRATION, ORAL; ANIMALS; ANTICHOLESTEREMIC AGENTS; CALLITHRIX; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; ENZYME INHIBITORS; HUMANS; INTRAMOLECULAR TRANSFERASES; LIPID METABOLISM; LIPIDS; LIVER; MALE; MICROSOMES; QUINUCLIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0033535515     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm990038q     Document Type: Article

References (22)

1. These results were reported, in part, orally at the Royal Society of Chemistry 8th Symposium on Medicinal Chemistry in Eastern England, Hatfield, U.K., April 17, 1997.
2. Shepherd, J.; Cobbe, S. M.; Ford, I.; Isles, C. G.; Lorimer, A. R.; Macfarlane, P. W.; McKillop, J. H.; Packard, C. J. Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia. New Engl. J. Med. 1995, 333, 1301-1307.
3. Pedersen, T. R.; Kjekshus, J.; Berg, K; Haghfelt, T.; Fargeman, O.; Thorgeirsson, G.; Pyorala, K.; Mertinen, T.; Olsson, A. G.; Wedel, H.; Wilhelmsmen, L. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994, 344, 1383-1389.
4. Adams, J. L.; Metcalf, B. Therapeutic Consequences of the Inhibition of Sterol Metabolism. Comprehensive Medicinal Chemistry; Sammes, P. G., Taylor, J. B., Eds.; Pergamon Press: Oxford, 1990; Vol. 2, pp 333-364.
5. Biller, S. A.; Neuenschwander, K.; Ponpipom, M. M.; Poulter, C. D. Squalene Synthase Inhibitors. Curr. Pharm. Des. 1996, 2, 1-40.
6. Alberts, A. W.; Berger, G. D.; Meade, B.; Bergstrom, J. D. Squalene Synthase Inhibitors. US Appl. 5135935. Chem. Abstr. 1982, 117, 245613.
7. Amin, D.; Morris, R. L.; Neuenschwander, K.; Scotese, A. C. Preparation of Azabicyclooctyloxymethylbenzenes and Related Compounds as Squalene Synthase Inhibitors. PCT Int. Appl. WO 9215579 AI 920917. Chem. Abstr. 1993, 118, 124402.
8. Brown, G. R.; Clarke, D. S.; Foubister, A. J.; Freeman, S.; Harrison, P. J.; Johnson, M. C.; Mallion, K. B.; McCormick, J.; McTaggart, F.; Reid, A. C.; Smith, G. J.; Taylor, M. J. Synthesis and Activity of a Novel Series of 3-Biarylquinuclidine Squalene Synthase Inhibitors. J. Med. Chem. 1996, 39, 2971-2979.
9. Brown, G. R.; Foubister, A. J.; Freeman, S.; McTaggart, F.; Mirrlees, D. R.; Reid, A. C.; Smith, G. J.; Taylor, M. J.; Thomason, D. A.; Whittamore, P. R. O. Novel Optimized Quinuclidine Squalene Synthase Inhibitors. Bioorg. Med. Chem. Lett. 1997, 7, 597-600.
10. Brittain, D. R.; Brown, G. R.; Mallion, K. B.; Whittamore, P. R. O. Quinuclidine derivatives useful as squalene synthase inhibitors and their preparation. Canada Pat. Appl. CA 2104981; Chem. Abstr. 1995, 122, 81124f.
11. Abe, I.; Tomesch, J. C.; Wattanasim, S.; Prestwich, G. D. Inhibitors of Squalene Biosynthesis and Metabolism. Nat. Prod. Rep. 1994, 11, 279-302.
12. Stach, D.; Zheng, Y. F.; Perez, A. L.; Oehlschlager, A. C.; Abe, I.; Prestwich, G. D.; Hartman, P. G. Synthesis and Inhibition Studies of Sulfur-Substituted Squalene Oxide Analogues as Mechanism-Based Inhibitors of 2,3-Oxidosqualene-Lanosterol Cyclase. J. Med. Chem. 1997, 40, 201-209.
13. Rose, I. G.; Sharpe, B. A.; Lee, R. C.; Griffin, J. H. Design Synthesis and In Vitro Evaluation of Pyridinium Ion Based Cyclase Inhibitors and Antifungal Agents. Bioorg. Med. Chem. 1996, 4, 97-103.
14. Abe, I.; Rhomer, M.; Prestwich, G. D. Enzymatic Cyclisation of Squalene and Oxidosqualene to Sterols and Triterpenes. Chem. Rev. 1993, 93, 2109-2206.
15. Eisele, B.; Budzinski, R.; Muller, P.; Maier, R.; Mark, M. Effects of a Novel 2,3-Oxidosqualene Cyclase Inhibitor on Cholesterol Biosynthesis and Lipid Metabolism In Vivo. J. Lipid Res. 1997, 38, 564-575.
16. Eisele, B.; Muller, P.; Maier, R., Mark, M. Effects of a Novel 2,3-Oxidosqualene Cyclase Inhibitor on the Regulation of Cholesterol Biosynthesis in HepG2 Cells. J. Lipid Res. 1996, 37, 148-158.
17. Morand, O. H.; Aebi, J. D.; Dehmlow, H.; Ji, Yu-H.; Cairns, N.; Lengfeld, H.; Himber, J. Ro 48-8071 a New 2,3-Oxidosqualene-Lanosterol Cyclase Inhibitor Lowering Plasma Cholesterol in Hamsters, Squirrrel Monkeys and Minipigs: Comparison to Simvastatin. J. Lipid Res. 1997, 38, 373-390.
18. Maier, R.; Mueller, P.; Woitun, E.; Hurnaus, B.; Mark, M.; Eisele, B.; Budzinski, R. M.; Hallermayer, G. Preparation and cholesterol biosynthesis inhibition activity of arylideneazacycloalkanes and their salts. Ger. Appl. DE 4325590 Chem. Abstr. 1994, 121, 108807.
19. Sternbach, L. H.; Kaiser, S. Antispasmodics 1. Bicyclic Basic Alcohols. J. Am. Chem. Soc. 1952, 74, 2215-2219.
20. Narayanan, K. V.; Swaminthan, S. The Rupe and Meyer-Schuster Rearrangements. Chem. Rev. 1971, 71, 429-438.
21. Ho, T.-L.; Wong, C. M. Cerric ammonium nitrate oxidation of diaryl sulphides. Synthesis 1972, 561-562.
22. CLOGP software for calculating logP was from Daylight Chemical Information Systems Inc., Daylight v 4.42.