City of Hope

Montefiore Medical Center

Samuel Rahbar

James Lester Figarola

Iraj Lalezari

David A Horne

Sanjay Awasthi

Christopher Lincoln

Rachael Mooney

John Termini

Timothy W Synold

Monika Polewski

George Somlo

Lixin Yang

Sharad S Singhal

Daniel Tamae

Gerald Wuenschell

Jyotasana Singhal

Jerry L Nadler

Parviz Lalezari

Rama Natarajan

One aspect of the disclosure relates to the use of derivatives of dichlorophenyl urea for treating cancers.

Compound for treating cancer and diabetes

Methods of quantifying N-carboxyethyl-2'-deoxyguanosine (CEdG) levels in biological samples and comparing those levels to known normal levels can diagnose a number of disorders, including diabetes and cancer. Methods can also determine whether therapies for disorders are effective by measuring CEdG levels before and after treatment. Measurement of CEdG levels occurs using liquid chromatography electrospray ionization tandem mass spectrometry.

Methods of quantifying N-(1-carboxyethyl)-2'-deoxy-guanosine (CEdG) and synthesis of oligonucleotides containing CEdG

Methods of quantifying a N-(1-carboxyethyl)-2'-deoxyguanosine (CEdG) levels in biological samples and comparing those levels to known normal levels can diagnose a number of metabolic disorders or complications associated therewith, including diabetes, its associated complications, and cancer. Methods can also determine whether therapies for disorders are effective by measuring CEdG levels before and after treatment. Measurement of CEdG levels is achieved by using liquid chromatography electrospray ionization tandem mass spectrometry.

One aspect of the disclosure relates to derivatives of aryl and heterocyclic ureido aryl and heterocyclic carboxamido isobutyric acids, dichlorophenyl urea, curcumin, and 1,3-diazetidine-2,4-dione, and pharmaceutical compositions thereof. The derivatives disclosed herein can modulate development of adipocytes and various cancer cells, including resistant cancer cells and cancer stem cells. Another aspect of the disclosure relates to the use of the derivatives and pharmaceutical compositions disclosed herein in treatment of obesity and various cancers.

Modulators of development of adipocyte and cancer cells

Methods of quantifying a N-carboxyethyl-2'-deoxyguanosine (CEdG) levels in biological samples and comparing those levels to known normal levels can diagnose a number of disorders, including diabetes and cancer. Methods can also determine whether therapies for disorders are effective by measuring CEdG levels before and after treatment. Measurement of CEdG levels occurs using liquid chromatography electrospray ionization tandem mass spectrometry.

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Accelerated formation of advanced glycation/lipoxidation end products (AGEs/ALEs) has been implicated in the pathogenesis of various diabetic complications. Several natural and synthetic compounds have been proposed and tested as inhibitors of AGE/ALE formation. We have previously reported the therapeutic effects of several new AGE/ALE inhibitors on the prevention of nephropathy and dyslipidemia in streptozotocin (STZ)-induced diabetic rats. In this study, we investigated the effects of various concentrations of LR-90 on the progression of renal disease and its effects on AGE and receptor for AGE (RAGE) protein expression on the kidneys of diabetic STZ-rats. In vitro studies were also performed to determine if LR-90 could inhibit the expression of various pro-inflammatory mediators in human monocytic cells.

Methods of suppression of rage gene expression and rage triggered inflammatory genes by selected age-inhibitors

The present invention provides methods for ameliorating, overcoming, or inhibiting insulin resistance in a subject, comprising administering to the subject an effective amount of a compound selected from the group consisting of LR-90 and LR-102, or a pharmaceutically acceptable salt or derivative thereof. Methods of treating type 2 diabetes and diabetic nephropathy, or preventing or slowing their development are also encompassed by the invention.

Use of LR-90 and LR-102 to overcome insulin resistance

This invention relates to methods for lowering lipid levels in mammals using compounds that inhibit advanced glycation endproducts (AGEs), LR-9, LR-74 and LR-90. These compounds, which inhibit non-enzymatic protein glycation, also inhibit the formation of advanced lipoxidation endproducts (ALES) on target proteins by trapping intermediates in glycoxidation and lopoxidation and inhibiting oxidation reactions important in the formation of AGEs and ALEs.

Methods of lowering lipid levels in a mammal

This invention relates to methods for lowering lipid levels in mammals using compounds that inhibit advanced glycation endproducts (AGEs), LR-9, LR-74 and LR-90. These compounds, which inhibit non-enzymatic protein glycation, also inhibit the formation of advanced lipoxidation endproducts (ALEs) on target proteins by trapping intermediates in glycoxidation and lopoxidation and inhibiting oxidation reactions important in the formation of AGEs and ALEs.

The nonenzymatic glycation and crosslinking of proteins is a part of the aging process with the glycation endproducts and crosslinking of long-lived proteins increasing with age. This process is increased at elevated concentrations of reducing sugars in the blood and in the intracellular environment such as occurs with diabetes. The structural and functional integrity of the affected molecules become disturbed by these modifications and can result in severe consequences. The compounds of the present invention can be used to inhibit this process of nonenzymatic glycation and therefore to inhibit some of the ill effects caused by diabetes or by aging. The compounds are also useful for preventing premature aging, spoilage of proteins in food and can prevent discoloration of teeth.

Inhibitors of formation of advanced glycation endproducts (AGEs)

Advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of a variety of debilitating diseases such as diabetes, atherosclerosis, Alzheimer's and rheumatoid arthritis, as well as in the normal aging process. Seven compounds are here reported to be active in breaking AGE-protein cross-links. These compounds are 1,4-benzene-bis&lsqb;4-methyleneaminophenoxyisobutyric acid&rsqb; (LR102); 4-&lsqb;(3,5-dichlorophenylureidophenoxyisobutyryl&rsqb;-4-aminobenzoic acid (LR99); L-bis-&lsqb;4-(4-chlorobenzamidophenoxyisobutyryl)cystine&rsqb; (LR20); 4-(3,5-dichlorophenylureido)phenoxyisobutyryl-1-amidocyclohexane-1-carboxylic acid (LR23); methylene bis &lsqb;4,4&prime;-(2-chlorophenylureidophenoxyisobutyric acid)&rsqb; (LR90); 5-aminosalicylic acid (5-ASA); and metformin. These compounds may be used to reverse the debilitating effects of those diseases in which AGEs are formed.

Breakers of advanced glycation endproducts

Pentoxifylline, pioglitazone and metformin have been found to inhibit the nonenzymatic glycation of proteins which often results in formation of advanced glycation endproducts and crosslinks. The nonenzymatic glycation and crosslinking of proteins is a part of the aging process with the glycation endproducts and crosslinking of long-lived proteins increasing with age. This process is increased at elevated concentrations of reducing sugars in the blood and in the intracellular environment such as occurs with diabetes. The structural and functional integrity of the affected molecules become perturbed by these modifications and can result in severe consequences. The compounds of the present invention can be used to inhibit this process of nonenzymatic glycation and therefore to inhibit some of the ill effects caused by diabetes or by aging. The compounds are also useful for preventing premature aging, rheumatoid arthritis, Alzheimer's disease, uremia, neurotoxicity, atherosclerosis and spoilage of proteins in food and can prevent discoloration of teeth.

Pentoxifylline, pioglitazone and metformin are inhibitors of formation of advanced glycation endproducts (AGE's)

The nonenzymatic glycation and crosslinking of proteins is a part of the aging process with the glycation endproducts and crosslinking of long-lived proteins increasing with age. This process is increased at elevated concentrations of reducing sugars in the blood and in the intracellular environment such as occurs with diabetes. The structural and functional integrity of the affected molecules become perturbed by these modifications and can result in severe consequences. The compounds of the present invention can be used to inhibit this process of nonenzymatic glycation and therefore to inhibit some of the ill effects caused by diabetes or by aging. The compounds are also useful for preventing premature aging, spoilage of proteins in food and can prevent discoloration of teeth.

Inhibitors of formation of advanced glycation endproducts (AGES)

Advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of a variety of debilitating diseases such as diabetes, atherosclerosis, Alzheimer's and rheumatoid arthritis, as well as in the normal aging process. Five compounds are here reported to be active in breaking AGE-protein cross-links. These compounds are L-bis-&lsqb;4-(4-chlorobenzamido-phenoxyisobutyryl)cystine&rsqb; (LR20); 4-(3,5-dichlorophenylureido)phenoxyisobutyryl-1-amido-cyclohexane-1-carboxylic acid (LR23); methylene bis &lsqb;4,4&prime;-(2-chlorophenylureido-phenoxyisobutyric acid)&rsqb; (LR90); 5-arninosalicylic acid (5-ASA); and metformin. These compounds may be used to reverse the debilitating effects of those diseases in which AGEs are formed.

Growing community of inventors

Beverly Hills, CA, United States of America

Samuel Rahbar