Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-05
1999-12-21
Mach, D. Margaret M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514 54, 514560, 514561, 514578, 514553, 514669, 514671, 514672, 514676, 514716, 514738, A61K 31535, A61K 3119, A61K 3113, A61K 31045
Patent
active
060049588
ABSTRACT:
The present invention is based on the discovery of a metabolic pathway in which a specific kinase converts fructose-lysine into fructose-lysine-3-phosphate in an ATP dependent reaction. Fructose-lysine-3-phosphate (FL3P) is then broken down to form free lysine, inorganic phosphate and 3-deoxyglucosone (3DG), the latter being a reactive protein modifying agent. 3DG can be detoxified by reduction to 3-deoxyfructose (3DF), or it can react with endogenous proteins to form advanced glycation end-product modified proteins (AGE-proteins), which are believed to be a cause of diabetic complications. Disclosed is a class of compounds which inhibit the action of FL3P kinase in the above-mentioned pathway. Also disclosed are therapeutic methods of using such inhibitors to reduce formation of AGE-proteins and thereby lessen, reduce and delay diabetic complications, as well as methods for assessing a diabetic's risk of developing complications and for determining the efficacy of the disclosed inhibitor therapy by measuring the ratio of 3DG to 3DF in a biological sample following an oral dose of a fructose-lysine-containing food product.
REFERENCES:
patent: 4371374 (1983-02-01), Cerami et al.
patent: 4761368 (1988-08-01), Cerami
patent: 4798583 (1989-01-01), Beck et al.
patent: 5108930 (1992-04-01), Ulrich et al.
patent: 5114943 (1992-05-01), Ulrich et al.
patent: 5128360 (1992-07-01), Cerami et al.
patent: 5130324 (1992-07-01), Ulrich et al.
patent: 5130337 (1992-07-01), Ulrich et al.
patent: 5221683 (1993-06-01), Ulrich et al.
patent: 5231031 (1993-07-01), Swzergold et al.
patent: 5243071 (1993-09-01), Ulrich et al.
patent: 5258381 (1993-11-01), Ulrich et al.
patent: 5262152 (1993-11-01), Ulrich et al.
patent: 5272165 (1993-12-01), Ulrich et al.
patent: 5318982 (1994-06-01), Ulrich et al.
patent: 5334617 (1994-08-01), Ulrich et al.
patent: 5358960 (1994-10-01), Ulrich et al.
patent: 5468777 (1995-11-01), France et al.
patent: 5476849 (1995-12-01), Ulrich et al.
Medline 97104279, abstract of Fouda, Biochemical Journal, Jun. 1995, 308(Pt3), pp. 815-822.
J.E. Tooke, "Perspectives in Diabetes Microvascular Function in Human Diabetes A Physiological Perspective", Diabetes, 44: 721-725 (1995).
V.M. Monnier et al., "Accelerated age-related browning of human collagen in diabetes mellitus", Proc. Natl. Acad. Sci. USA, 81: 583-587 (1984).
J.H. Lee et al., "Glycosylation of Lens Proteins in Senile Cataract and Diabetes Mellitus", Biochem. Biophys. Res. Comm., 123: 888-893 (1984).
R.L. Engerman et al., "Progression of Incipient Diabetic Retinopathy During Good Glycemic Control", Diabetes, 36: 808-812 (1987).
C. R. Harrington et al., "A glycation connection", Nature, 370: 247-248 (1994).
K. H. Knecht et al., Detection of 3-Deoxyfructose and 3-Deoxyglucosone in Human Urine and Plasma: Evidence for Intermediate Stages of the Maillard Reaction In Vivo, Archives of Biochem. Biophys., 294: 130-137 (1992).
S. Reddy et al., "N.sup..epsilon. -(Carboxymethyl)lysine is a Dominant Advanced Glycation End Product (AGE) Antigen in Tissue Proteins", Biochem, 34: 10872-10878 (1995).
T. Ikeda et al., N.sup..epsilon. -(Carboxymethyl)lysine Protein Adduct is a Major Immunological Epitope in Proteins Modified with Advanced Glycation End Products of the Maillard Reaction, Biochem., 35: 8075-8083 (1996).
R. G. Khalifah et al., Kinetics of Nonenzymatic Glycation of Ribonuclease a Leading to Advanced Glycation End Products. Paradoxical Inhibition by Ribose Leads to Facile Isolation to Protein Intermediate for Rapid-Post-Amadori Studies, Biochemistry., 35: 4645-4654 (1996).
M. Brownlee et al., "Advanced Glycosylation End Products in Tissue and the Biochemical Basis of Diabetic Complications", The New England Journal of Medicine, 318: 1315-1321 (1988).
M. Brownlee et al., "Glycation and Diabetic Complications", Diabetes, 43: 836-841 (1994).
M. Brownlee et al., "Glycation Products and the Pathogeniesis of Diabetic Complications", Diabetes Care, 15: 1835-1843 (1992).
T. Niwa et al., Elevated Serum Levels of 3-Deoxyglucosone, a Potent Protein-Cross-Linking Intermediate of the Maillard Reaction, in Uremic Patients, Nephron, 69: 438-443 (1995).
W. L. Dills, Jr., "Protein fructosylation: Fructose and the MaillardREaction", Am. J. Clin. Nutr., 58: 779S-787S (1993).
H. Yamada et al., "Increase in 3-Deoxyglucosine Levels in Diabetic Rat Plasma", J. Biol. Chem., 269: 20275-20280 (1994).
N. Igaki et al., "Effects of 3-Deoxyglucosone on the Maillard Reaction", Clin. Chem., 36: 631-634 (1990).
M. Takahashi et al., "In Vivo Glycation of Aldehyde Reductase, a Major 3- Deoxyglucosone Reducing Enzyme: Identification of Glycation Sites", Biochem., 34: 1433 (1995).
E. Fujii et al., "The Presence of 2-Keto-3-deoxygluconic Acid and Oxoaldehyde Dehydrogenase Activity in Human Erythrocytes", Biochem. Biophys. Res. Comm., 210: 852-857 (1995).
O. Barski et al., "Mechanism of Human Aldehyde Reductase: Characterization of the Active Site Pocket", Biochem., 34: 11264-11275 (1995).
F. Kappler et al., "Phosphorylated Amadori Products in Mammalian Kidneys", Abstract presented at the Maillard Symposium, Aug. 29 to Sep. 1, 1993.
B. Su et al., "Identification of Tagatoselysine-3-Phosphate in Hyperglycemic Kidneys", Abstracts presented at the American Society of Nephrology Conference, Oct. 26-29, 1994.
F. Kappler et al., "Metabolism of Fructoselysine in the Kidney", Abstract presented at the American Society of Nephrology Meeting, Nov. 3-6, 1996.
B. Su et al., "Metabolism of Fructoselysine in the Kidney", Abstract presented at the International Society of Magnetic Resonance Meeting, Apr. 27 to May 3, 1996.
B. S. Szwergold et al., "Identification of a Novel Phosphononester from Mammalian Kidneys as a Secondary Phosphate Ester of Fructosyl-Lysine", Abstract presented at the International Society of Magnetic Resonance, Aug. 14-20, 1993.
Fox Chase Cancer Center Scientific Report, pp. 190-195 (1990-1991).
Fox Chase Cancer Center Scientific Report, pp. 214-217 (1991-1992).
Fox Chase Cancer Center Scientific Report, pp. 203-205 (1992-1993).
Fox Chase Cancer Center Scientific Report, pp. 175-178 (1993-1994).
Fox Chase Cancer Center Scientific Report, pp. 183-186 (1995).
A. Petersen et al., "Fructose metabolism in the human erythrocyte", Biochem. 284: 363-366 (1992).
S. Lal et al., "Metabolism of Fructose-3-phosphate in the Diabetic Rat Lens", Archives of Biochem. Biophys., 318: 191-199 (1995).
B. Szwergold et al., "Identification of Fructose-3-phosphate in the Lens of Diabetic Rats", Science, 247: 451-454 (1990).
S. Lal et al., "Production of Fructose and Fructose-3-phosphate in Maturing Rat Lenses", Investigative Ophthalmology & Visual Science, 36: 969-973 (1995).
B. Szwergold et al., .sup.31 P-Nuclear Magnetic Resonance Evidence of an Activated Hexose-Monophosphate Shunt in Hyperglycemic Rat Lenses In Vivo, Diabetes, 44: 810-815 (1995).
F. Kappler et al., "Identification of Galactitol 2-Phosphate and Galactitol 3-Phosphate in the Lens of Galactose-Fed Rats", Metabolism, 44: 1527-1531 (1995).
Brown Truman R.
Kappler Francis
Lal Sundeep
Su Bangying
Szwergold Benjamin
Fox Chase Cancer Center
M. Mach D. Margaret
LandOfFree
Compounds and methods for therapeutic intervention in preventing does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Compounds and methods for therapeutic intervention in preventing, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compounds and methods for therapeutic intervention in preventing will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-505361