Post-Amadori inhibitors of advanced glycation reactions

Details Post-Amadori inhibitors of advanced glycation reactions Post-Amadori inhibitors of advanced glycation reactions

2001-10-19

2003-08-26

Balasubramanian, Venkataraman (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S256000, C544S333000, C514S256000, C514S269000, C514S340000, C514S341000, C514S345000, C514S349000

Reexamination Certificate

active

06610852

ABSTRACT:

FIELD OF THE INVENTION
The instant invention is in the field of inhibition of Advanced Glycation End-products formation, and the treatment and prevention of chronic tissue damage and diabetic complications.
BACKGROUND OF THE INVENTION
The elucidation of the pathogenic mechanisms of hyperglycemia is critical for developing rational therapy for the prevention of chronic tissue damage and diabetic complications, such as proteinuria, impaired glomerular clearance, nephropathy leading to end stage renal disease, protein cross-linking, retinopathy, and atherosclerotic disease. However, there is no consensus at present on the relative importance of the different possible pathogenic mechanisms that potentially contribute to these diabetic complications.
Nonenzymatic glycation by glucose and other reducing sugars is an important post-translational modification of proteins that has been increasingly implicated in diverse pathologies. Irreversible, nonenzymatic glycation and crosslinking through a slow, glucose-induced process may mediate many of the complications associated with diabetes. Chronic hyperglycemia associated with diabetes can cause chronic tissue damage which can lead to complications such as retinopathy, nephropathy, and atherosclerotic disease. (Cohen and Ziyadeh, 1996,
J. Amer. Soc. Nephrol.
7:183-190). Clinically, diabetic nephropathy is defined by the presence of:
1. decrease in renal function (impaired glomerular clearance)
2. an increase in urinary protein (proteinuria)
3. the simultaneous presence of hypertension.
Nonenzymatic glycation of proteins, lipids, and nucleic acids may also play an important role in the natural processes of aging. Recently, protein glycation has been associated with &bgr;-amyloid deposits and formation of neurofibrillary tangles in Alzheimer disease, and possibly other neurodegenerative diseases involving amyloidosis (Colaco and Harrington, 1994,
NeuroReport
5: 859-861). Glycated proteins have also been shown to be toxic, antigenic, and capable of triggering cellular injury responses after uptake by specific cellular receptors (see for example, Vlassara, Bucala & Striker, 1994,
Lab. Invest.
70:138-151; Vlassara et al., 1994,
PNAS
(
USA
) 91:11704-11708; Daniels & Hauser, 1992,
Diabetes
41:1415-1421; Brownlee, 1994,
Diabetes
43:836-841; Cohen et al., 1994,
Kidney Int.
45:1673-1679; Brett et al., 1993,
Am. J. Path.
143:1699-1712; and Yan et al., 1994,
PNAS
(
USA
) 91:7787-7791).
It has been shown that the resulting chronic tissue damage associated with long-term diabetes mellitus arise in part from in situ immune complex formation by accumulated immunoglobulins and/or antigens bound to long-lived structural proteins that have undergone Advanced Glycosylation End-product (AGE) formation, via non-enzymatic glycosylation (Brownlee et al., 1983,
J. Exp. Med.
158:1739-1744).
It has also been demonstrated that formation of AGE products occurs in dialysis fluid in vitro. (Lamb et al., Kidney Intl. 47:1768-1774 (1995). Furthermore, the level of various AGE species is increased in blood of patients on maintenance hemodialysis (Motomiya et al., Kidney Intl. 54:1357-1366 (1998)), and various studies indicate that glycosylation of peritoneal components occurs during peritoneal dialysis. (See. for example, Friedlander et al., J. Clin. Invest. 1996. 97:728-735; Nakayama et al., Kidney Intl. 51:182-186 (1997); and Korbet et al., Am. J. Kidney Disease 22:588-591 (1993) These studies have implicated accumulation of AGEs in the following pathologies in patients receiving dialysis:
1. Increased cardiac morbidity and mortality (Korbet et al., 1993)
2. Dialysis-related amyloidosis (Motomiya et al., Kidney Intl. 54:1357-1366, (1998)
3. Increased permeability of the peritoneal membrane (Nakayama et al., 1997)
4. Renal failure progression (Dawnay and Millar, Cell. Mol. Biol. 44:1081-1094 (1998) (increased rate to end-stage renal disease)
5. Ultrafiltration failure and peritoneal membrane destruction (Linden et al., Perit. Dial. Int. 18:290-293 (1998).
FIG. 1
is a flow chart of the glycation pathways seen in vitro with high sugar concentrations. Schiff bases and Amadori compounds are referred to as “early intermediates/products”, while post-Amadori rearrangements leading to AGEs are referred to as “late intermediates/products” in these pathways. (See also U.S. Pat. No. 5,985,857.) The Amadori intermediates represent a crucial juncture where the “classical” pathway of nonenzymatic glycation begins to become essentially irreversible. In early inhibition studies, “glycation” was usually measured either as Schiff base formed (after reduction with labeled cyanoborohydride) or as Amadori product formed (after acid precipitation using labeled sugar). Such assays do not yield information on inhibition of post-Amadori conversion steps to “late” post-Amadori AGE products, since such steps lead to no change in the amount of labeled sugar that is attached to the proteins. Other “glycation” assays have relied on the sugar-induced increase of non-specific protein fluorescence, but this can also be induced by dicarbonyl oxidative fragments of free sugar, such as glycoaldehyde or glyoxal (Hunt et al., 1988,
Biochem.
256:205-212), independently of Amadori product formation.
We have previously disclosed the use of pyridoxamine and derivative compounds to inhibit the conversion of Amadori compounds to post Amadori AGEs and to treat and prevent chronic tissue damage and diabetic complications such as proteinuria, impaired glomerular clearance, diabetic nephropathy, and protein cross-linking. (U.S. Pat. No. 5,985,857 and U.S. patent application Ser. No. 08/971,285 (filed Nov. 17, 1997) and Ser. No. 09/322,569 (filed May 28, 1999), all references herein incorporated in their entirety.) We have also previously shown that pyridoxamine inhibits the formation of AGEs in peritoneal dialysis fluid (U.S. patent application Ser. No. 60/127,906, filed Apr. 6, 1999).
However, there remains a need in the art for novel compounds and methods for inhibiting AGE formation and for treating and preventing chronic tissue damage and diabetic complications.
SUMMARY OF THE INVENTION
The present invention provides novel compounds, pharmaceutical compositions, methods, kits, and dialysis solutions for inhibiting the conversion of Amadori compounds to post Amadori advanced glycation endproducts, for treating and preventing chronic tissue damage and diabetic complications, and for inhibiting dialysis-related pathologies, each method comprising administering to a mammal an amount effective to cause the desired effect of a compound of the following general formula:
wherein
R1, R1′, R5, and R5′ are independently selected from the group consisting of (CH
2
)
n
X wherein n is between 0 and 6 and X is H, OH, SH, COOH or NH
2
; and mono-, di-, or tri-halogenated C1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkenyl; with the proviso that at least one R1, R1′, R5, and R5′ is selected from the group consisting of OH, SH, and NH
2
;
wherein R2, R2′, R4 and R4′ are independently selected from the group consisting of (CH2)
n
Z, wherein n has the meaning given above and Z is H, OH, SH, COOH, or NH
2
; and mono-, di-, or tri-halogenated C1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkenyl;
wherein R3 and R3′ are independently selected from the group consisting of H and mono-, di-, or tri-halogenated C1-6 alkyl;
wherein R6 and R6′′ are (CH
2
)x, wherein x is between 1 and 6;
wherein R7 is selected from NH and HOP═O;
or wherein R6, R6′, and R7 combine to form an aryl group, heteroaryl group, or
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.


REFERENCES:
Buffoni et al. J. Enzyme Inhibition 8, 267-279, 1995.

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