Pyrrolopyridinium derivatives

Details Pyrrolopyridinium derivatives Pyrrolopyridinium derivatives

2001-02-28

2003-09-02

Ceperley, Mary E. (Department: 1641)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving antigen-antibody binding, specific binding protein...

C424S093200, C436S171000, C436S172000, C436S501000, C436S503000, C436S811000, C436S815000, C530S388250, C530S388900, C530S389300, C530S389800, C546S083000, C546S113000

Reexamination Certificate

active

06613537

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel pyrrolopyridinium derivatives; an antibody prepared from said derivatives as a hapten; a method for the diagnosis of diseases including diabetes, diabetic complications, amyoidosis, renal failure, dialysis-related complications, aging, and diseases accompanied by aging, such as Alzheimer's disease, etc. by measuring said derivative or by measuring reactivity in the subject with an antibody prepared therefrom; and a method for evaluating the effectiveness of pharmaceuticals which are effective for treating diabetes, diabetic complications, amyloidosis, renal failure, dialysis-related complications, aging, and diseases accompanied by aging, such as Alzheimer's disease, etc.
BACKGROUND OF THE INVENTION
In 1968, glycosylhemoglobin (HbAlc), which is one of the minor components of hemoglobin was identified in vivo and was found to increase in patients diagnosed as having diabetes. With this discovery, the Maillard reaction was shown to occur with proteins in vivo. Despite having been studied mainly in the field of food chemicals, the biological and medical meaning of the Maillard reaction would now receive greatly increased public attention.
The Maillard reaction may be classified into a former stage and a latter stage. In the former stage, a Schiff base is formed by the condensation of an amino group of a protein with an aldehyde group of a reducing sugar and is stabilized as a result of the Amadori rearrangement. In the latter stage, the rearranged Schiff Base is transferred, after a long series of reactions, to an Advanced Glycation Endproduct (AGE). The latter stage end products are characterized by fluorescence, a color change to brown and molecular crosslinking. In recent years, several studies on AGE have investigated the relationship between various diseases and AGE, which is produced particularly in the advanced stages of various diseases.
Several studies have uncovered the participation of AGE in various diseases and in the aging process. See “AGE (glycation) and Diseases” (BIO Clinica, 11(5), p. 314 (1996)), which is a review by Dr. Horiuchi et al. For example, aging is thought to be a process in which various proteins and DNA in tissues are modified or changed until they can no longer be decomposed and removed. The protein and DNA so-modified are accumulated in the body, resulting in a loss of their function. The advanced glycation of tissue proteins is exemplified as one of the causes thereof. In fact, it has been shown that the fluorescence of the hydrolyzed products of skin collagen and lens protein increases with aging and that an excessive advanced glycation of lens proteins participates in the onset of cataracts. In addition, AGE is now being recognized as one of the causes of the aging phenomenon because advanced glycation causes an inhibition of enzymatic activity and a corresponding decrease in the body's ability to decompose intracellular protein. AGE also causes a substance transport disorder brought on by advancedly glycated cytoskeleton protein and DNA mutation caused by a cross-linkage formed between DNA and protein by AGE.
Studies using an antibody to the above-mentioned AGE have uncovered the participation of AGE in various diseases. Still other reports show that an anti-AGE antibody reacts in a concentration-dependent manner with the water-soluble fraction and the alkali-soluble fraction of the normal human lens crystallin, while a very high correlation is observed between anti-AGE antibody reactivity and the aging process; that advanced glycation in the Descemet membrane and lens vesicle of cattle increases with age, as shown by immune electric microscopy; and that the AGE immunoreaction with the petrosal nerve cell correlates with aging, as shown by an immunohistochemical investigation using an antibody.
Fluorescence, which is characteristic of the presence of AGE, is used as an indicator for investigating the correlation between AGE and various diseases. It is known that in diabetic patients fluorescence is significantly higher than it is in healthy people. Moreover, the accumulation of AGE was reported in renal tissues, such as the renal mesangium region, blood vessel walls and urinary tubules, and in the coronary arteriosclerotic nest of diabetic patients. It was also reported that, as a result of immune staining using an anti-AGE antibody, AGE shows almost the same distribution in the peripheral nerves of both experimental diabetic rats and human diabetics. Accordingly, it has been recognized that there is a correlation between diabetes mellitus and AGE.
It has also been shown that an excessive formation of AGE in an organism is a cause of diabetic complications. For example, an advanced glycation of crystallin, which is a lens protein, is one of the causes of diabetic cataracts. It has also been shown that AGE is deeply related to diabetic nephropathy. The glomerular basement membrane in the kidney, comprised of collagen, is advancedly glycated by hyperglycemia and is apt to be bound to albumin, immunoglobulin, and low-density lipoprotein, etc., whereby the basement membrane thickens, thus disturbing the renal filtration function. In addition, reports suggest that AGE may accumulate in mesangium cells and that it may participate in inflammation, such as the secretion of cytokines mediated by a receptor. Recently, it has been reported that a suppressor for the production of AGE is useful in treating diabetic nephropathy. It has been also reported that the myelin protein of a nerve cell is advancedly glycated, suggesting that AGE participates in diabetic neuropathy as well. From these reports, a clear correlation emerges between increased amounts of AGE in the body and the onset of diabetic complications such as diabetic nephropathy, arteriosclerosis, neurosis, retinopathy, cataracts, etc. AGE and diabetic complications are summarized, for example, in a review entitled “AGE and Diabetic Complications” (Saishin Igaku, 49, 2, p. 248 (1994)) by Morisaki, et al.
In addition, a relation between AGE and dialysis-related amyloidosis has been found because fluorescence increases in the protein found in the sera of dialyzed patients. A similar accumulation of AGE occurs at the site where a sediment forms in the amyloid of the carpal tunnel of dialyzed patients.
A recent report suggests that a scavenger receptor recognizing the AGE protein is present in monocytes, macrophages, mesangium cells and endothelial cells, and that the AGE recognition mediated by such a receptor results in the release of cytokine, the promotion of blood vessel permeability, abnormal blood flow, etc. A relationship thus emerges between AGE and the symptoms of inflammation, capillary obstruction, arteriosclerosis, etc. Furthermore, it is suspected that AGE participates in the onset and progress of Alzheimer's disease because AGE is strongly detected in senile plaque, and in amyloid and neurofibril changes which are characteristically noted in the brains of patients suffering from Alzheimer disease.
The Maillard reaction may also generate free radical oxygen. Free radical or active oxygen is receiving much recent public attention as a cause of aging, tissue disorders resulting from diabetes mellitus and the generation of pathological changes resulting from Alzheimer's disease. It is becoming clear that the Amadori compound produced by the initial-stage reaction of the Maillard reaction is oxidized by active oxygen to produce AGE, while at the same time causing the generation of active oxygen. It has been also reported in neuromatous cell strains (SK—N—SH) that neurofibril (PHF) tau-protein generates active oxygen by glycation and that it activates the transcription factor NF—&kgr;B. It has also been suggested that an extinction enzyme for active oxygen such as Cu—Zn-superoxide dismutase (Cu—Zn-SOD) is advancedly glycated as its activity lowers with aging. Such glycation of Cu—Zn-SOD becomes over time an essential cause for an increase in oxidative stress and suggests again the relation between Alzhei

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