Inhibitors of cholesterol esterase

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Patent

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

549295, 549324, C07D30758, C07D30932

Patent

active

060342552

ABSTRACT:
The present invention provides novel haloenol lactones that are effective as active site inhibitors of cholesterol esterase. By inhibiting cholesterol esterase the inhibitors of the present invention provide a new approach to the treatment of hypercholesterolemia through limiting the bioavailability of dietary cholesterol.

REFERENCES:
patent: 3227736 (1966-01-01), Tschesche et al.
patent: 3346594 (1967-10-01), Merijan et al.
patent: 4338122 (1982-07-01), Wheeler
patent: 5025017 (1991-06-01), Karanewsky
patent: 5059696 (1991-10-01), Anderson et al.
patent: 5210228 (1993-05-01), Todd et al.
Rai, R. and Katzenellenbogen, J.A., J. Med. Chem., 1992, 35, 4150-4159.
Gordon, T., Kannel, W.B., Castelli, W.P., Dawber, T.R., Lipoprotein, cardiovascular disease, and death: the Framingham Study. Arch Intern Med 141, 1128-1131 (1981).
Hsu, L. Spinier, S.A., Johnson, N.E., Comparative evaluation of the safety and efficacy of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Ann Pharmacotherapy 29, 743-759 (1995).
Boumendil, E., Tubert-Bitter, P., Depression-induced absenteeism in relations to antihyperlipidemic treatment: a study using GAZEL cohort data. Epidemiology 6, 322-325 (1995).
Phan, T., McLeod, J.G., Pollard, J.D., Peiris, O., Rohan, A., Halpern, J.P., Peripheral neuropathy associated with simvastatin. J Neurology, Neurosurgery & Psychiatry 58, 625-628 (1995).
Gallo, L.L., Ghiang, Y., Vahouny, G.V., Treadwell, C.R., Localization and origin of rat intestinal cholesterol esterase determined by immunocytochemistry. J Lipid Res 28, 537-545 (1980).
Daniels, S.B., Cooney, E., Sofia, M.J., Chakravarty, P.K., Katzenellenbogen J.A., Haloenol lactones. Potent enzyme-activated irreversible inhibitors for .alpha.-chymotrypsin. J Biol Chem 250, 15046-15053 (1983).
Li, F., Huang, Y., Hui, D.Y., Bile salt stimulated cholesterol esterase increases uptake of high density lipoprotein-associated cholesteryl esters by HepG2 cells. Biochem 35, 6657-6663 (1996).
Myers-Payne, S.C., Hui, D.Y., Brockman, H.L., Schroeder, F., Cholesterol esterase: a cholesterol transfer protein. Biochem 34, 3942-3947 (1995).
Lopez-Candates, A., Bosner, M.S., Spilburg, C.A., Lange, L G., Cholesterol transport function of pancreatic cholesterol esterase: directed sterol uptake and esterification in enterocytes. Bio Chem 32 32, 12085-12089 (1993).
Spilburg, C.A., Cox, D.G., Wang, X., Bernat, B.A., Bosner, M.S., Lange, L.G., Identifcation of a species specific regulatory site in human pancreatic cholesterol esterase. Biochem 34, 15532-15538 (1995).
Kumar, B.V., Alema-Gomez, J.A., Colwell, N., Lopez-Candales, A., Bosner, M.S., Spilburg, C.A., Lowe, M., Lange, L.G., Structure of the human pancreatic cholesterol esterase. Biochem 31, 6077-6081 (1992).
DiPersio, L.P., Fontaine, R.N., Hui, D.Y., Site-specific directed mutagenesis of an essential histidine residue in pancreatic cholesterol esterase. J Biol Chem 266, 4033-4036 (1991).
Stein, R., Strimpler, A., Edwards, P., Lewis, J., Mauger, R., Schwartz, J., Stein, M., Trainor, D., Wildonger, R. and Zottola, M., Mechanism of Slow-Binding Inhibition of Human Leukocyte Elastase by Trifluoromethyl Ketones. Biochemistry 26, 2682-2689 (1987).
Trainor, D., Wildonger, R. and Zottola, M., Mechanism of Slow-Binding Inhibition of Human Leukocyte Elastase by Trifluoromethyl Ketones. Biochemistry 26, 2682-2689 (1987).
Imperiali, B. and Abeles, R. Inhibition of Serine Proteases by Peptidyl Fluoromethyl Ketones. Biochemistry 25, 3760-3767 (1986).
Gelb, M., Svaren, J. and Abeles, R., Fluoroketone Inhibitors of Hydrolytic Enzymes. Biochemistry 24, 1813-1817 (1985).
Brodbeck, U., Schweikert, K., Gentinella, R. and Rottenberg, M., Fluorinated Aldehydes and Ketones acting as Quasi-substrate Inhibitors of Acetylcholinesterase. Biochem. Biophys. Acta, 567, 357-369 (1979).
Dafforn, A., Neenan, J., Ash, C., Betts, L., Finke, J., Garman, J., Rao, M., Walsh, K. and Williams, R. Acetylcholinesterase Inhibition by the Ketone Transition State Analogs Phenoxyacetone and 1-Halo-3-phenoxy-2-propanones. Biochem Biophys. Res. Commun. 104, 597-602 (1982).
Abeles, R.H., Suicide Enzyme Inactivators. C&EN, Sep. 19, 48-56 (1983).
Boulanger, W.A. and Katzenellenbogen, J.A., Structure-Activity Study of 6-Substituted 2-Pyranones as Inactivators of .alpha.-Chymotrypsin. J. Med. Chem., 29, 1159-1163 (1986).
Thole, F.B. and Thorpe, J.F., The Chemistry of Glutaconic Acids. Part II. The Reactions of the Alkylglutaconic Acids Having One Mobile Hydrogen Atom. J. Chem. Soc., 99, 2208-2241 (1911).
The Chemistry of Glutaconic Acids. Part I. Ibid. 99, 2187-2208 (1911).
Westkaemper and Abeles, R.H., Inactivators of Serine Proteases Based on 6-Chloro-2-pyrone. Biochemistry, 22, 3256-3264 (1983).
Daniels, S.B. and Katzenellenbogen, J.A., Halo Enol Lactones: Studies on the Mechanism of Inactivation of .alpha.-Chymotrypsin. Biochemistry, 25, 1436-1441 (1986).
Chakravarty, P.K., Krafft, G.A. and Katzenellenbogen, J.A., Haloenol Lactones: Enzyme-activated Irreversible Inactivators for Serine Proteases. J. Biol, Chem. 257, 610-612 (1982).
Krafft, G.A. and Katzenellenbogen, J.A., Synthesis of Halo Enol Lactones. Mechanism-Based Inactivators of Serine Proteases. J. Am. Chem. Soc., 103, 5459-5466 (1981).
Vaugnan, W.R., Craven, R.L., Little, R.Q. and Schoenthaler, A.C., Addition of Hydrogen Halides to .alpha. .beta.-Unsaturated Acids. J. Am. Chem. Soc., 77, 1594-1598 (1955).
Dai, W. and Katzenellenbogen, J.A., Stereoselective Z- and E- Bromo Enol Lactonization of Alkynoic Acids. J. Org. Chem., 56, 6893-6896 (1991).
Moreno-Manas et al., "Palladium-Catalyzed C-Alkylations of the Highly Acidic and Enolic Triacetic Acid Lactone. Mechanism and Stereochemistry," J. Org. Chem., 1988, vol. 53, pp. 5328-5335, especially p. 5330.
Arcadi et al., "Palladium-Catalyzed Reaction of Vinyl Triflates and Vinyl/Aryl Halides with 4-Alkynoic acids: Regio-and Stereoselective Synthesis of (E-delta-Vinyl/aryl-gamma-methylene-gamma-butyrolactones." J. Org. Chem., 1992, vol. 57, pp. 976-982, especially pp. 976 and 978.
Yamamoto, M. "Cyclisation of Acetylenecarboxylic acid. Synthesis of gamma-Methylene-butyrolactones." J. Chem. Soc., Perkin Trans. I., 1981, vol. 2, pp. 582-588, especially p. 583.

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Inhibitors of cholesterol esterase does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Inhibitors of cholesterol esterase, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Inhibitors of cholesterol esterase will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-364584

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.