Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-07-08
2002-03-12
Fay, Zohren (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S538000, C514S570000
Reexamination Certificate
active
06355680
ABSTRACT:
TECHNICAL FIELD OF INVENTION
The present invention is directed to the discovery of compositions that inhibit the nonenzymatic attachment of glucose to albumin, preventing the formation of glycated albumin. The compounds are useful in preventing and treating disorders of the kidney and other organs that result from deleterious effects of glycated albumin.
BACKGROUND OF THE INVENTION
Glycated albumin, which is formed by the condensation of glucose with reactive protein amino groups, adversely affects capillary function, structure and metabolism. Experimental studies have shown that this glycated protein has distinct biologic effects that the nonglycated counterpart does not possess. These effects include facilitated transport across capillary filtration barriers and hyperfiltration in the kidney, and stimulation of nitric oxide synthase and nitric oxide production, increased synthesis of extracellular matrix proteins, and activation of cytokine and growth factor systems in kidney and vascular tissue. These and other biologic effects of glycated albumin have been described in numerous scientific publications including
Kidney International
42:875-881, 1992;
Lab Investigation
51:27-35, 1997;
Kidney International
45:475-484, 1994;
Molecular & Cellular Biochemistry
125:19-25, 1993;
Molecular & Cellular Biochemistry
151:61-67, 1995;
Kidney International
53:631-638, 1998.
The described biologic activities are observed with concentrations of glycated albumin that found in clinical specimens from human subjects, and do not depend on elevated glucose concentrations to be operative. Since the circulating half-life of albumin in humans is 17 days, there is prolonged exposure of vascular beds to the glycated protein after it is formed.
The use of agents that block the effects of glycated albumin to ameliorate vascular pathologies has been explored in several scientific studies (
Kidney International
45:1673-1679, 1994;
Journal of Clinical Investigation
95:2338-2345, 1995;
Diabetologia
39:270-274, 1996;
Journal of Diabetic Complications
12:28-33, 1998). Such agents may be monoclonal antibodies or other molecules that react specifically with fructosyllysine residues that are present on glycated albumin but are not present on nonglycated albumin, and which are disclosed in U.S. Pat. Nos. 5,223,392 and 5,518,720, incorporated by reference herein. Such therapies have been shown, among other things, to prevent the structural and functional changes characteristic of renal and retinal microvascular disease. Anti-glycated albumin therapy therefore has been proposed as a treatment modality for vascular pathologies.
A novel approach to prevent pathologies related to the biologic effects of glycated albumin would be to reduce the formation of the glycated protein and to lower its concentration in the circulation. This could be accomplished by administering compounds that, by binding to specific sites in albumin, can inhibit the attachment of glucose to physiologically important lysine amino groups. The compounds would achieve this desired effect by obscuring the reactive lysine amino group and/or causing a conformational shift in the tertiary structure of the albumin molecule that renders the important glycatable site inaccessible.
Identification of compounds which prevent glycation at physiologically important sites is difficult to accomplish and has not been described in the art. In vitro glycation is distinctly different from in vivo glycation. Excessive concentrations of glucose or reducing carbohydrate are used, and the number of sites that undergo glycation is significantly increased relative to sites which are subject to glycation in vivo. Physiologically important sites are only a small subset of the total number of sites and cannot be distinguished from the unimportant ones after in vitro glycation according to methods described in the art.
Binding to albumin is a likely prerequisite for a compound to prevent glycation of albumin and many compounds of diverse structural classes have been shown to bind to albumin at various sites. Examples include: vitamin C, vitamin E, vitamin B
6
, diclofenac, acetylsalicylic acid, warfarin, bilirubin, iodobenzoic acids, diazepam, digitoxin, clofibrate, methotrexate, lithium, phenobarbital, cyclosporin benzodiazepine, paracetamol, ibuprofen, suprofen, aminodarone, propanolol, griseofulvan, and others. But binding to albumin is not sufficient for antiglycation activity. Only a few compounds have been reported to influence the condensation of carbohydrate with reactive protein amino groups in vitro, and none of them have been shown to affect lysine amino groups that are physiologically important in vivo or to be of therapeutic benefit when administered in vivo with respect to glycation-related pathologies (
Biochemical & Biophysical Research Communications
165:991-996, 1988;
Life Sciences
43:1725-1731, 1988;
Diabete & Metabolisme
14:40-42, 1988;
Biochemica et Biophysica Acta
1120:201-204, 1992; Diabetes 41:167-173, 1992). Moreover, the conditions employed in such in vitro studies are irrelevant to in vivo conditions as to degree of glycation, the reducing sugar and concentration used, and the concentration of compound tested. Binding to albumin and inhibition of in vitro glycation is not synonymous with prevention of glycation at physiologically important sites.
It is a finding of the present invention that many compounds bind to albumin and inhibit glycation at unimportant sites but do not prevent glycation at physiologically important sites.
It is another finding of the present invention that agents that bind to fructosyllysine residues on albumin and, in so doing, prevent pathobiologic effects of glycated albumin provide a useful tool for elucidating which albumin binding ligands are potentially important in preventing the formation of glycated sites that are pathophysiologically important.
The present invention is directed toward discovery of albumin-binding compounds that block non-enzymatic glycation of physiologically important sites which, when glycated, lead to vascular pathologies. The present invention is further directed to methods of use of these novel agents for the treatment of glycation-related pathologies, and novel methods of synthesis of these agents.
SUMMARY OF THE INVENTION
The present invention provides novel compounds that inhibit the nonenzymatic glycation of albumin at physiologically relevant sites.
The present invention also provides improved methods of synthesis of 2-phenylamino-phenylacetic acid derivatives.
The present invention further provides novel compositions for preventing and treating glycation-induced pathologies.
These and other objects of the invention are achieved with the discovery of compounds that are reactive with domain(s) in human albumin that are susceptible to nonenzymatic glycation in vivo; that, by binding to the sites in the structure of albumin, protect the protein from attachment to glucose.
DETAILED DESCRIPTION
The present invention evolved from the finding that glycation-associated pathologies can be ameliorated by ligand compounds that bind to specific glycated sites on albumin. A novel finding of the present invention is that these ligands can be used to identify other compounds that prevent glycation of pathophysiologically important sites in the albumin molecule that are selectively subject to glycation in vivo and that, when glycated, cause deleterious biologic effects in relevant tissues. The present invention further finds that these compounds can be identified by their ability to prevent, in their binding to albumin, the formation of fructosyllysine epitopes in glycated albumin that are recognized by monoclonal antibodies that are site selective for fructosyl-lysine residues that are known to be involved in glycation-associated pathologies.
It is a finding of the present invention that compounds are identified that, by binding to human albumin and protecting the protein from nonenzymatic glycation at pathophysiologically important sites, are therapeutically useful for the
Caesar, Rivise, Bernstein, Cohen & Pokitilow, Ltd.
Exocell Inc.
Fay Zohren
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