WO2009051804A1 - Composés de thiazolium destinés au traitement ou à la prévention de maladies associées à une résistance à l'insuline - Google Patents

Composés de thiazolium destinés au traitement ou à la prévention de maladies associées à une résistance à l'insuline Download PDF

Info

Publication number
WO2009051804A1
WO2009051804A1 PCT/US2008/011886 US2008011886W WO2009051804A1 WO 2009051804 A1 WO2009051804 A1 WO 2009051804A1 US 2008011886 W US2008011886 W US 2008011886W WO 2009051804 A1 WO2009051804 A1 WO 2009051804A1
Authority
WO
WIPO (PCT)
Prior art keywords
age
insulin
glucose
diabetes
rsa
Prior art date
Application number
PCT/US2008/011886
Other languages
English (en)
Inventor
Josephine Forbes
David Tong
Sofianos Andrikopoulos
Mark Cooper
Original Assignee
Synvista Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synvista Therapeutics, Inc. filed Critical Synvista Therapeutics, Inc.
Publication of WO2009051804A1 publication Critical patent/WO2009051804A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • disturbances include insulin resistance and ⁇ cell dysfunction, which are characteristic of diseases such as metabolic syndrome (syndrome X), types I and II diabetes and pre-diabetes, diseases that are rapidly growing in number in the western world.
  • diseases are multi-factorial and their mechanism or physiology are, in the majority of cases, not well characterized or understood.
  • Diabetes is a disease derived from multiple causative factors and characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test.
  • type I diabetes or insulin-dependent diabetes mellitus (IDDM)
  • IDDM insulin-dependent diabetes mellitus
  • Type I diabetes formerly known as insulin-dependent diabetes (IDDM)
  • childhood diabetes or also known as juvenile diabetes is characterized by loss of the insulin-producing beta cells of the islets of Langerhans of the pancreas leading to a deficiency of insulin.
  • preventative measure that can be taken against type I diabetes.
  • Most people affected by type I diabetes are otherwise healthy and of a healthy weight when onset occurs.
  • Type I diabetes Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. This type of diabetes comprises up to 10% of total cases in North America and Europe, though this varies by geographical location. This type of diabetes can affect children or adults but was traditionally termed "juvenile diabetes" because it represents a majority of cases of diabetes affecting children.
  • the main cause of beta cell loss leading to type I diabetes is a T-cell mediated autoimmune attack.
  • the principal treatment of type I diabetes even from the earliest stages, is replacement of insulin. Without insulin, ketosis and diabetic ketoacidosis can develop and coma or death will result.
  • type II diabetes or noninsulin-dependent diabetes mellitus (NIDDM)
  • NIDDM noninsulin-dependent diabetes mellitus
  • hyperinsulinemia elevated plasma insulin levels
  • these patients are insulin resistant, which means that they have a resistance to the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues.
  • Some patients are insulin resistant, but not diabetic. These patients compensate for the insulin resistance by secreting more insulin, so that serum glucose levels are not elevated enough to meet the criteria of type II diabetes.
  • In patients with type II diabetes even elevated plasma insulin levels are insufficient to overcome the pronounced insulin resistance. Persistent or uncontrolled hyperglycemia that occurs with diabetes is associated with increased and premature morbidity and mortality.
  • abnormal glucose homeostasis is associated both directly and indirectly with obesity, hypertension, and alterations of the lipid, lipoprotein and apolipoprotein metabolism, as well as other metabolic and hemodynamic disease.
  • Patients with type II diabetes have a significantly increased risk of macro vascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension are critically important in the clinical management and treatment of type II diabetes.
  • Many patients who have insulin resistance or type II diabetes often have several symptoms that together are referred to as syndrome X, or the metabolic syndrome.
  • a patient having this syndrome is characterized as having three or more symptoms selected from the following group of five symptoms: abdominal obesity, hypertriglyceridemia, low high- density lipoprotein cholesterol (HDL), high blood pressure, and elevated fasting glucose, which may be in the range characteristic of type II diabetes if the patient is also diabetic.
  • Each of these symptoms is defined in the recently released Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NIH Publication No. 01-3670.
  • Patients with metabolic syndrome whether or not they have or develop overt diabetes mellitus, have an increased risk of developing the macrovascular and microvascular complications that are listed above that occur with type II diabetes, such as atherosclerosis and coronary heart disease.
  • Insulin resistance is not primarily caused by a diminished number of insulin receptors but by a post-insulin receptor binding defect that is not yet completely understood. This lack of responsiveness to insulin results in insufficient insulin-mediated activation of uptake, oxidation and storage of glucose in muscle and inadequate insulin-mediated repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
  • a widely used drug treatment involves the administration of meglitinide or a sulfonylurea (e.g. tolbutamide or glipizide), which are insulin secretagogues. These drugs increase the plasma level of insulin by stimulating the pancreatic beta-cells to secrete more insulin.
  • meglitinide or a sulfonylurea e.g. tolbutamide or glipizide
  • the amount of insulin in the body can be supplemented by the injection of insulin so that insulin concentrations are high enough to stimulate even the very insulin-resistant tissues.
  • dangerously low levels of plasma glucose can result from administration of insulin and/or insulin secretagogues, and an increased level of insulin resistance due to the even higher plasma insulin levels can occur.
  • Pre-diabetes is a condition in which blood glucose levels are higher than normal but not high enough for a diagnosis of diabetes. Pre-diabetes is also called impaired fasting glucose or impaired glucose tolerance. Many people with pre-diabetes develop type II diabetes within 10 years. In addition, they are at risk for heart disease and stroke.
  • Advanced glycation the biochemical non-enzymatic modification of proteins by reducing sugars [Fu, M.X. et al. Glycation, glycoxidation, and cross-linking of collagen by glucose. Kinetics, mechanisms, and inhibition of late stages of the Maillard reaction. Diabetes 43, 676-683 (1994)], has been extensively assessed as a promoter of the progressive complications seen in diabetes [Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813-20 (2001)].
  • tissue and circulating advanced glycation end products (AGEs) accumulate over time in natural aging, however this is accelerated as the result of redox imbalances or hyperglycaemia seen in diabetes.
  • an important exogenous source of AGEs in the absence of hyperglycaemia is from the Western diet, primarily from pasteurised dairy foods, bakery products and "browned" foodstuffs such as coffee and meat [Koschinsky, T. et al. Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy. Proc Natl Acad Sci USA 94, 6474-9 (1997); Vlassara, H. et al. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc Natl Acad Sci USA 99, 15596-601 (2002)] or from smoking [Cerami, C. et al.
  • Tobacco smoke is a source of toxic reactive glycation products.
  • Maillard reactions were traditionally considered to contribute to flavour, texture and color in food preparation (e.g. in roasted meat, coffee or toast), food technologists and manufacturers are now also using this reaction to add functional properties (e.g. improved emulsification and gel formation) to a wide variety of foods.
  • functional properties e.g. improved emulsification and gel formation
  • AGEs can exert their biological effects via receptors such as the receptor for advanced glycation end products (RAGE) [Chavakis, T. et al.
  • the pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med 198, 1507-15 (2003)].
  • RAGE is a multi-ligand receptor involved in the amplification of immune and inflammatory responses primarily via nuclear factor -KB
  • NF-KB chemokines and cytokines which ultimately recruit inflammatory cells.
  • a recent study has identified blockade of the late stages of autoimmune diabetes with the "decoy" soluble RAGE receptor [Bierhaus, A. et al. Diabetes- associated sustained activation of the transcription factor nuclear factor-kappaB. Diabetes 50, 2792-808 (2001)].
  • Another study has suggested that polymorphisms of the RAGE gene may be important to the heritability of insulin resistance [Sullivan, CM. et al. RAGE polymorphisms and the heritability of insulin resistance: the Leeds family study. Diab Vase Dis Res 2, 42-4 (2005).
  • the present invention provides methods of treating, or ameliorating a symptom of, a disease, disorder or condition associated with insulin resistance or ⁇ -cell dysfunction in a patient in need thereof, comprising administering a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt of the compound of Formula I,
  • R 1 and R 2 are selected from the group consisting of hydrogen, hydroxy (lower) alkyl, acetoxy (lower) alkyl, lower alkyl, lower alkenyl; or R and R together with their ring carbons may be an aromatic fused ring, optionally substituted by one or more amino, halo or alkylenedioxy groups;
  • Z is hydrogen or an amino group;
  • Y is amino, a group of the formula:
  • R is a lower alkyl, alkoxy, hydroxy, amino or an aryl group, said aryl group optionally substituted by one or more lower alkyl, lower alkoxy, halo, dialkylamino, hydroxy, nitro or alkylenedioxy groups; a group of the formula: -CH 2 R' wherein R' is hydrogen, or a lower alkyl, lower alkenyl, or aryl group; or a group of the formula: wherein R" is hydrogen and R" is a lower alkyl group, optionally substituted by an aryl group, or an aryl group, said aryl group optionally substituted by one or more lower alkyl, halo, or alkoxylcarbonyl groups; or R" and R'" are both lower alkyl groups; and
  • X is a pharmaceutically acceptable anion, and a pharmaceutically acceptable carrier, thereby treating said disease, disorder or condition associated with insulin resistance or ⁇ -cell dysfunction.
  • the method can further include administering a inhibitor of a receptor for advanced glycation end-products (RAGE).
  • RAGE advanced glycation end-products
  • the RAGE inhibitor can be soluble RAGE.
  • Rl and R2 can be independently lower alkyl.
  • Z can be hydrogen.
  • R can be an aryl group.
  • the compound of Formula I can be 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium.
  • the compound of Formula I is 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride or 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide.
  • the disease, disorder or condition associated with insulin resistance or ⁇ -cell dysfunction can be type I diabetes, non-insulin dependent (type II) diabetes, pre-diabetes or metabolic syndrome.
  • Administration of a pharmaceutical composition comprising a compound of Formula I can increase insulin sensitivity, can ameliorate insulin resistance, can ameliorate plasma insulin and glucose levels, can suppresses basal insulin secretion, can increase acute insulin secretion, can reduce plasma methylglyoxal levels and/or can reduce mitochondrial oxidative stress.
  • a method for the treatment or prevention of diseases associated with insulin resistance and/or ⁇ cell dysfunction using compounds and compositions of the invention is disclosed.
  • Diseases associated with insulin resistance and/or ⁇ cell dysfunction include insulin resistance, type I diabetes, type II diabetes, pre-diabetes, and metabolic syndrome.
  • the compositions of the invention include pharmaceutical compositions comprising compounds for inhibiting the formation of and reversing the pre-formed advanced glycosylation (glycation) endproducts and breaking the subsequent cross-links.
  • the breaking of the pre-formed advanced glycosylation (glycation) endproducts and cross-links is a result of the cleavage of a dicarbonyl-based protein crosslinks present in the advanced glycosylation endproducts.
  • the methods and compositions of this invention are thus directed to compounds which, by their ability to affect such cleavage, can be utilized to break the pre-formed advanced glycosylation endproduct and cross-link, and the resultant deleterious effects thereof, both in vitro and in vivo.
  • treatment directed against AGEs may be useful for the treatment, reduction of risk in the development and prevention of diseases related to insulin resistance and/or ⁇ cell dysfunction.
  • the invention includes a method of treating or reducing the risk of developing or preventing one or more diseases, disorders, or conditions selected from the group consisting of insulin resistance, type I diabetes, non-insulin dependent diabetes (type II diabetes), prediabetes, and metabolic syndrome, the method comprising the administration of an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxy(lower)alkyl, acetoxy(lower)alkyl, lower alkyl, lower alkenyl, or R 1 and R 2 together with their ring carbons may be an aromatic fused ring, optionally substituted by one or more amino, halo or alkylenedioxy groups;
  • Z is hydrogen or an amino group;
  • Y is amino, a group of the formula:
  • R is a lower alkyl, alkoxy, hydroxy, amino or an aryl group, said aryl group optionally substituted by one or more lower alkyl, lower alkoxy, halo, dialkylamino, hydroxy, nitro or alkylenedioxy groups; a group of the formula: -CH 2 R' wherein R' is hydrogen, or a lower alkyl, lower alkynyl, or aryl group; or a group of the formula:
  • R" 1 wherein R" is hydrogen and R'" is a lower alkyl group, optionally substituted by an aryl group, or an aryl group, said aryl group optionally substituted by one or more lower alkyl, halo, or alkoxylcarbonyl groups; or R" and R'" are both lower alkyl groups;
  • X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion; and mixtures thereof, and a carrier therefor.
  • the invention includes a method of treating or reducing the risk of developing or preventing non-insulin dependent (type II) diabetes in a patient in need of such treatment, by administering to the patient a therapeutically or prophylactically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the invention includes a method of treating or reducing the risk of developing or preventing type I diabetes in a patient in need of such treatment, by administering to said patient a therapeutically or prophylactically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the invention includes a method of treating or reducing the risk of developing or preventing insulin resistance in a patient in need of such treatment, by administering to said patient a therapeutically or prophylactically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the invention includes a method of treating or reducing the risk of developing or preventing pre-diabetes in a patient in need of such treatment, by administering to said patient a therapeutically or prophylactially effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the invention includes a method of treating or reducing the risk of developing or preventing metabolic syndrome in a patient in need of such treatment by administering to said patient a therapeutically or prophylactically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the invention includes the method of the invention, wherein the treatment increases the insulin sensitivity of the patient.
  • the invention includes a compound of formula I, wherein R 1 is lower alkyl.
  • the invention includes a compound, wherein R 2 is lower alkyl.
  • the invention includes a compound, where in R 1 and R 2 are lower alkyl.
  • the invention includes a compound, wherein Z is H.
  • the invention includes a compound, wherein Y is a group of the formula - CH 2 C(O)R.
  • the invention includes a compound, wherein R is aryl group.
  • the invention includes a compound, wherein R is phenyl.
  • the invention includes a compound, wherein X is halo.
  • the invention includes a compound, wherein halo is chloride.
  • the invention includes a method of treating or reducing the risk of developing or preventing one or more diseases, disorders, or conditions selected from the group consisting of insulin resistance, type I diabetes, non-insulin dependent diabetes (type ⁇ diabetes), pre- diabetes, and metabolic syndrome, the method comprising the administration of an effective amount of the compound alagebrium or a pharmaceutically acceptable salt thereof.
  • the invention includes the compound alagebrium chloride.
  • the invention includes a method of ameliorating insulin resistance in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said insulin resistance.
  • the invention includes a method of ameliorating plasma insulin and glucose levels in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said plasma insulin and glucose levels.
  • the invention includes a method of suppressing basal insulin hypersecretion and stimulating acute insulin secretion in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby suppressing said basal insulin hypersecretion and stimulating said acute insulin secretion.
  • FIGURE 1 is a series of bar graphs that illustrate that exposure of MIN6N8 cells to advanced glycation end products causes insulin secretory defects independent to glucose concentrations.
  • Figure Ia shows the effect on basal insulin secretion of MIN6N8 cells upon exposure to AGEs in normal and high glucose and the effect of alagebrium.
  • Figure Ib shows the effect on glucose stimulated insulin secretion (GSIS) for cells grown in high glucose conditions as compared to cells grown in normal glucose and the effect of alagebrium.
  • GSIS glucose stimulated insulin secretion
  • Figure Ic shows flow cytometry analysis for cell surface RAGE.
  • Figure Id shows basal insulin secretion for MIN6N8 cells that were transiently transfected with human full length RAGE or the control vector pCIneo, for 7 days in 25 mM glucose.
  • Figure Ie shows 2OmM GSIS for MIN6N8 cells that were transiently transfected with human full length RAGE or the control vector pCIneo, for 7 days in 25 mM glucose.
  • FIGURE 2 is a series of bar graphs which illustrate that AGEs disrupt glucose stimulated insulin secretion by uncoupling, interruption of ATP production, Ca2+ flux and superoxide production.
  • Figure 2a shows the effect on ATP content in cells grown in high glucose upon exposure to AGE-BSA, and alagebrium.
  • Figure 2b shows the effect on calcium flux in MIN6N8 cells grown in high glucose and treated with AGE-BSA, alagebrium (ALT), and verapamil (VER).
  • Figure 2c shows the effect on superoxide production in mitochondria isolated from MIN6N8 cells grown in high glucose and treated with AGE-BSA and alagebrium.
  • Figure 2d shows the effect on UCP-2 mRNA expression in cells treated with AGE-BSA and alagebrium.
  • Figure 2e shows the effect of siRNA to UCP-2 on insulin secretion in cells treated with AGE-BSA.
  • FIGURE 3 is a series of graphs which illustrate that short-term infusion of AGE-RSA into healthy rats induces early ⁇ cell decompensation.
  • Figure 3 a shows the effect on plasma insulin in rodents following short term infusion of AGE-RSA.
  • Figure 3b shows the effect on the gene expression of proinsulin within the pancreas in rodents following short term infusion of AGE-RSA.
  • Figure 3c shows the effect on the number of proliferating ⁇ cells within islets in rodents following short term infusion of AGE-RSA.
  • Figure 3d shows the effect on the islet AGE (CML) content within islets in rodents following short term infusion of AGE-RSA.
  • CML islet AGE
  • FIGURE 4 is a series of graphs which illustrate that long term infusion of AGE-RSA into healthy rats interrupts first phase insulin secretion and induces ⁇ cell death.
  • Figure 4a shows the effect on plasma insulin in rats following long term infusion of AGE-RSA and treatment with alagebrium.
  • Figure 4b shows the effect on proinsulin gene expression in rats following long term infusion of AGE-RSA and treatment with alagebrium.
  • Figure 4c shows the effect on the islet AGE (CML) content within islets in rats following long term infusion of AGE-RSA and treatment with alagebrium.
  • CML islet AGE
  • Figure 4d shows the effect on ED-I monocyte/macrophage cellular infiltration within pancreatic islets in rats following long term infusion of AGE-RSA and treatment with alagebrium.
  • Figure 4e shows the effect on ⁇ cell death within islets in rats following long term infusion of AGE-RSA and treatment with alagebrium.
  • FIGURE 5 is a series of graphs which illustrate that a high dietary intake of AGEs causes insulin deficiency, secretory defects, and hyperglycaemia.
  • Figure 5a shows fasting plasma insulin and glucose levels at 6 months.
  • Figure 5b shows insulin levels before and during i.v. glucose challenge.
  • Figure 5c shows proinsulin gene expression by real time RT- PCR.
  • Figure 5d shows islet RAGE expression by immunohistochemistry.
  • Figure 5e shows islet AGE (CML) content by immunohistochemistry.
  • FIGURE 6 is a series of graphs which illustrate that a high dietary intake of AGEs causes insulin deficiency and hyperglycaemia.
  • Figure 6a shows the difference in dietary AGE (CML) intake between low AGE and high AGE containing diets.
  • Figure 6b shows the difference in circulating AGEs (CMLs) found in rats receiving a high AGE diet verses a low AGE diet.
  • Figure 6c shows the difference in fasting plasma glucose found in rats receiving a high AGE diet verses a low AGE diet.
  • Figure 6d shows the difference in fasting plasma insulin levels found in rats receiving a high AGE diet verses a low AGE diet.
  • FIGURE 7 is a series of bar graphs which illustrate an acute insulin secretory experiment using MIN6N8 cells treated with AGE-BSA, BSA only and AGE-BSA + ALT- 711 at different time points (30min, 60 min, 2h and 4 h).
  • Figure 7A shows the effect on basal insulin secretion.
  • Figure 7B shows the effect on acute insulin secretion.
  • Figure 7C shows the effect on total insulin secretion.
  • Figure 7D shows the effect on cellular insulin.
  • FIGURE 8 is a series of graphs which illustrate in vivo insulin resistance data.
  • Figure 8A shows plasma insulin concentrations over time following an intraperitoneal bolus of glucose given at 16 weeks.
  • Figure 8B shows AUC insulin to AUC glucose ratio.
  • Figure 8C shows fasting plasma glucose and insulin data.
  • RAGE mediates a novel proinflammatory axis: a central cell surface receptor for SlOO/calgranulin polypeptides.
  • Sandu, O. et al. Insulin resistance and type 2 diabetes in high-fat-fed mice are linked to high glycotoxin intake. Diabetes 54, 2314-9 (2005)] although the cellular and molecular mechanism responsible for this damage has not been previously examined.
  • AGE infusion in healthy non-diabetic rats had profound and progressive effects on first phase insulin secretion and caused ⁇ cell decompensation, in association with activation of classical pathways invoked in the destruction of pancreatic islet ⁇ cells. This included recruitment of monocytes and macrophages which may have been mediated via RAGE. Each of these abnormalities was attenuated with an anti-AGE therapy, alagebrium. Furthermore, consumption of diets high in AGE content by healthy rats also caused insulin secretory defects in the context of insulin deficiency and hyperglycaemia.
  • One aspect of the invention includes a method of ameliorating first phase insulin secretion in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said first phase insulin secretion.
  • Another aspect of the invention includes a method of ameliorating the destruction of pancreatic islet ⁇ cells in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said destruction of pancreatic islet ⁇ cells.
  • Another aspect of the invention includes a method of ameliorating the recruitment of monocytes and macrophages in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said recruitment of monocytes and macrophages.
  • Another aspect of the invention includes a method of reducing levels of ED-I monocyte/macrophage infiltration in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby reducing said levels of ED-I monocyte/macrophate infiltration.
  • One aspect of the invention includes a method of ameliorating insulin secretory defects in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said insulin secretory defects.
  • the insulin secretory defect is basal hypersecretion of insulin. In another aspect the insulin secretory defect is decreased glucose stimulated insulin secretion (GSIS).
  • GSIS glucose stimulated insulin secretion
  • Another aspect of the invention includes a method of ameliorating cellular uptake of glucose in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating cellular uptake of glucose. In one aspect, the cellular uptake is AGE-induced.
  • Another aspect of the invention includes a method of ameliorating RAGE expression in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating RAGE expression.
  • AGEs administered exogenously to rodents provided a simplified in vivo model, without potentially confounding effects of hyperglycaemia, to study the direct effects of AGEs per se on islet function.
  • the exogenous concentrations given led to increases in ⁇ cell CML (a prevalent AGE) concentrations at both time-points studied.
  • ⁇ cell CML a prevalent AGE
  • islet CML accumulation was associated with progressive loss of first phase insulin secretion and initially ⁇ cell compensation, but was subsequently followed by decompensation.
  • proliferation of pancreatic ⁇ cells was evident, in association with elevated proinsulin gene expression, in conjunction with up-regulation of islet RAGE expression.
  • acute 1 st phase insulin secretion had significantly declined.
  • ⁇ cells also had reduced proinsulin and insulin expression and had elevations in RAGE expression.
  • chronic AGE infusion had an impact on ⁇ cell death demonstrated by increases in TUNEL staining in some islets within the present study.
  • These functional molecular and structural changes provide strong evidence of progressive ⁇ cell damage and importantly were all prevented with AGE-lowering therapy with alagebrium.
  • This ability of alagebrium to attenuate AGE induced ⁇ cell injury suggests that the AGE-RAGE axis is an excellent target for therapeutic strategies to prevent, retard or reverse progressive ⁇ cell injury as the result of nutrient excess and in particular increased intake of dietary AGEs glycotoxins.
  • One aspect of the invention includes a method of ameliorating ⁇ cell damage in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said ⁇ cell damage.
  • Another aspect of the invention includes a method of ameliorating ⁇ cell CML levels in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said ⁇ cell CML levels.
  • Another aspect of the invention includes a method of ameliorating proinsulin and/or insulin expression in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said proinsulin and insulin expression.
  • One aspect of the invention includes a method of ameliorating insulin sensitivity in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said insulin sensitivity.
  • Ligand engagement of RAGE is known to induce oxidative stress [Bierhaus, A. et al.
  • One aspect of the invention includes a method of ameliorating oxidative stress in cells in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said oxidative stress.
  • Another aspect of the invention includes a method of ameliorating mitochondrial superoxide production in cells in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said mitochondrial superoxide production.
  • Another aspect of the invention includes a method of ameliorating UCP-2 expression in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said UCP- 2 expression.
  • Another aspect of the invention includes a method of ameliorating cellular ATP content in cells in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said cellular ATP content.
  • Another aspect of the invention includes ameliorating ATP depletion in cells in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said ATP depletion.
  • Impaired calcium flux in ⁇ cells has previously been implicated as contributing to insulin secretory dysfunction [Sakurada, M. et al. Relation between glucose-stimulated insulin secretion and intracellular calcium accumulation studied with a superfusion system of a glucose-responsive pancreatic beta-cell line MIN6. Endocrinology 132, 2659-65 (1993)] which is relevant to AGE induced ⁇ cell dysfunction since AGEs in the present examples were shown to interfere with cellular calcium flux. Indeed AGEs per se have been shown to interfere with cellular calcium flux in other settings [Mene, P. et al. Effects of advanced glycation end products on cytosolic Ca2+ signaling of cultured human mesangial cells.
  • One aspect of the invention includes a method of ameliorating cellular calcium flux in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said cellular calcium flux.
  • One aspect of the invention includes a method of ameliorating the number of RAGE positive ⁇ cells in a patient in need thereof, by administering a pharmaceutical composition of the invention, thereby ameliorating said number of RAGE positive ⁇ cells.
  • glycotoxic AGEs contribute to the pathogenesis of progressive insulin secretory defects and decline of insulin producing pancreatic islet ⁇ cells. Indeed, supporting data have been presented from in vitro studies in cells, rodent models and susceptible human populations. There is also compelling evidence from experiments using alagebrium, an AGE cross-link breaker which reduced islet AGE accumulation. Taken together, this series of studies presents a modifiable risk factor for type II diabetes and insulin secretory defects, which may be a novel therapeutic target able to be addressed using compounds and/or compositions of the invention which reduce AGE accumulation.
  • the compounds and compositions of the invention may be used to treat a variety of diseases including these listed below: a method for treating or controlling or reducing the risk of developing non-insulin dependent diabetes mellitus (type II diabetes) in a human or other mammalian patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of the invention; a method for treating or controlling or reducing the risk of developing metabolic syndrome in a human or other mammalian patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of the invention; a method for treating or controlling or reducing the risk of developing insulin resistance in a human or other mammalian patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of the invention; a method for treating or controlling or reducing the risk of developing type I diabetes in a human or other mammalian patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of the invention; a method for treating or controlling or
  • the compounds and compositions of the invention may be used to prevent a variety of diseases from occurring, including the diseases listed below: a method for preventing non-insulin dependent diabetes mellitus (type II diabetes) in a human or other mammalian patient by administering to the patient a prophylatically effective amount of a compound of the invention; a method for preventing the metabolic syndrome in a human or other mammalian patient by administering to the patient a prophylactically effective amount of a compound of the invention; a method for preventing insulin resistance in a human or other mammalian patient by administering to the patient a prophylactically effective amount of a compound of the invention; a method for preventing type I diabetes in a human or other mammalian patient by administering to the patient a prophylactically effective amount of a compound of the invention; a method for preventing pre-diabetes in a human or other mammalian patient by administering to the patient a prophylactically effective amount of the compound of the invention.
  • the invention comprises the use of thiazolium compounds having the following structural formula:
  • R 1 is selected from the group consisting of hydrogen, hydroxy (lower) alkyl, acetoxy (lower) alkyl, lower alkyl, lower alkenyl;
  • R 2 is selected from the group consisting of hydrogen, hydroxy (lower) alkyl, acetoxy (lower) alkyl, lower alkyl, lower alkenyl; or R 1 and R 2 together with their ring carbons may be an aromatic fused ring, optionally substituted by one or more amino, halo or alkylenedioxy groups;
  • Z is hydrogen or an amino group
  • Y is amino, a group of the formula: o
  • R is a lower alkyl, alkoxy, hydroxy, amino or an aryl group, said aryl group optionally substituted by one or more lower alkyl, lower alkoxy, halo, dialkylamino, hydroxy, nitro or alkylenedioxy groups; a group of the formula :
  • R' is hydrogen, or a lower alkyl, lower alkenyl, or aryl group; or a group of the formula:
  • R" is hydrogen and R'" is a lower alkyl group, optionally substituted by an aryl group, or an aryl group, said aryl group optionally substituted by one or more lower alkyl, halo, or alkoxylcarbonyl groups; or R" and R'" are both lower alkyl groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion;
  • the preferred thiazolium compound of the instant invention comprises the structure of formula I, wherein R 1 and R 2 are lower alkyl, Z is hydrogen, Y is a group of the formula
  • the compound of the invention is 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride or N- ⁇ henacyl-4,5-dimethylthiazolium chloride, also referred to as ALT-711 or alagebrium chloride herein.
  • the compound of the invention is 3-(2-phenyl-2- oxoethyl)-4,5-dimethylthiazolium bromide or N-phenacyl-4,5-dimethylthiazolium bromide, also referred to as DMPTB or PMTB.
  • the invention includes the use of a pharmaceutical composition comprising a compound of the formulae of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of the formulae of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the compounds, and their compositions, utilized in this invention appear to react with an early glycosylation product thereby preventing the same from later forming the advanced glycosylation end products which lead to cross-links, and thereby, to molecular or protein aging and other adverse molecular consequences. Additionally, the compounds react with already formed advanced glycosylation end products to reduce the amount of such products.
  • the invention additionally comprises an analytic method for identifying compounds for the treatment or prevention of diseases such as type I and type II diabetes, metabolic syndrome, and insulin resistance.
  • the method determines the "breaking" or reversal of the formation of non-enzymatic endproducts.
  • the invention further extends to the identification and use of a novel cross-link structure which is believed to represent a significant number of the molecular crosslinks that form in vitro and in vivo as a consequence of advanced glycation.
  • the cross-link structure includes a sugar-derived ⁇ -dicarbonyl segment or moiety, such as a diketone, that is capable of cleavage by a dinucleophilic, thiazolium-like compound.
  • the cross-link structure may be according to the formula shown below:
  • a and B independently, are sites of attachment to the nucleophilic atom of a biomolecule.
  • diseases such as type I and type II diabetes, metabolic syndrome, and/or insulin resistance
  • diseases such as type I and type II diabetes, metabolic syndrome, and/or insulin resistance, e.g., complications that arise from a reduction of nNOS expression which prevents the rearrangement and cross-linking of early glycosylation products to form the advanced glycosylation endproducts.
  • the compound of the invention is administered prophylatically or therapeutically.
  • compositions including pharmaceutical compositions, incorporating the compounds of the present invention.
  • lower alkyl or “Ci ⁇ linear alkyl” means that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms and includes methyl, ethyl, propyl, butyl, pentyl, and hexyl and the corresponding branched and cycloalkyl isomers thereof.
  • Ci -6 linear alkyl means that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms and includes methyl, ethyl, propyl, butyl, pentyl, and hexyl.
  • Ci - 6 branched alkyl means that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms in a branched arrangement, and includes e.g., isopropyl and isobutyl.
  • Ci -6 cycloalkyl alkyl means that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms in a cyclic arrangement, and includes e.g., cyclopentyl and cyclohexyl
  • lower alkynyl means that the group contains from 2, 3, 4, 5, or 6 carbon atoms.
  • lower alkoxy means that the group contains from 1, 2, 3, 4, 5, or 6 carbon atoms, and includes methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy, and the corresponding branched-chain isomers thereof. These groups are optionally substituted by one or more halo, hydroxy, amino or lower alkylamino groups.
  • lower acyloxy(lower)alkyl means that the acyloxy portion contains from 2, 3, 4, 5, or 6 carbon atoms and the lower alkyl portion contains from 1, 2, 3, 4, 5, or 6 carbon atoms.
  • Typical acyloxy portions are those such as acetoxy or ethanoyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, and the corresponding branched chain isomers thereof.
  • Typical lower alkyl portions are as described hereinabove.
  • aryl groups or "C 6 -CiO aryl" encompassed by the formulae of the invention are those containing 6, 7, 8, 9, or 10 carbon atoms, such as naphthyl, phenyl and lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and are optionally substituted by 1-2 halo, hydroxy, lower alkoxy or di (lower) alkylamino groups.
  • Preferred aryl groups are phenyl, methoxyphenyl and 4-bromophenyl groups.
  • halo atoms in the formulae of the invention may be fluoro, chloro, bromo or iodo.
  • the compounds of the invention are formed as biologically and pharmaceutically acceptable salts.
  • Useful salt forms are the halides, particularly the bromide and chloride, tosylate, methanesulfonate, and mesitylenesulfonate salts.
  • Other related salts can be formed using similarly non-toxic, and biologically and pharmaceutically acceptable anions.
  • the preferred thiazolium compound of the instant invention comprises the structure of formula I, wherein R 1 and R 2 are lower alkyl, Z is hydrogen, Y is a group of the formula O Il
  • the compound of the invention is 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride or N- phenacyl-4,5-dimethylthiazolium chloride, also referred to as ALT-711 or algebrium chloride herein.
  • the compound of the invention is 3-(2-phenyl-2-oxoethyl)-4,5- dimethylthiazolium bromide or N-phenacyl-4,5-dimethylthiazolium bromide, also referred to as DMPTB or PMTB.
  • treating includes any effect e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.
  • Treating or “treatment” of a disease state means the treatment of a disease- state in a mammal, particularly in a human, and include: (a) inhibiting an existing disease- state, i.e., arresting its development or its clinical symptoms; and/or (c) relieving the disease- state, i.e., causing regression of the disease state.
  • preventing means causing the clinical symptoms of the disease state not to develop i.e., inhibiting the onset of disease, in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
  • Preventing the disease from developing means prophylatically treating the diease.
  • Representative compounds of the present invention are: 3-aminothiazolium mesitylenesulfonate; 3-amino-4,5-dimethylaminothiazolium mesitylenesulfonate; 2,3-diaminothiazoliniurn mesitylenesulfonate; 3 -(2-methoxy-2-oxoethyl)-thiazolium bromide; 3-(2-methoxy-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3 -(2-methoxy-2 -oxoethyl)-4-methylthiazolium bromide; 3-(2-phenyl-2-oxoethyl)-4-methylthiazolium bromide; 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride; 3-amino-4
  • Compounds of the invention further include those compounds represented by the formula Ia:
  • R is independently selected from the group consisting of hydrogen, hydroxy(lower)alkyl, acetoxy(lower)alkyl, lower alkyl, lower alkenyl
  • R 2 is independently selected from the group consisting of hydrogen, hydroxy(lower)alkyl, acetoxy(lower)alkyl, lower alkyl, lower alkenyl, or R 1 and R 2 together with their ring carbons may be an aromatic fused ring, optionally substituted by one or more amino, halo or alkylenedioxy groups;
  • Z is hydrogen or an amino group
  • Y is amino, a group of the formula
  • Il -CH 2 C-R wherein R is a lower alkyl, alkoxy, hydroxy, amino or an aryl group, said aryl group optionally substituted by one or more lower alkyl, lower alkoxy, halo, dialkylamino, hydroxy, nitro or alkylenedioxy groups; a group of the formula -CH 2 R' wherein R' is hydrogen, or a 'lower alkyl, lower alkynyl, or aryl group; or a group of the formula
  • R" is hydrogen and R'" is a lower alkyl group, optionally substituted by an aryl group, or an aryl group, said aryl group optionally substituted by one or more lower alkyl, halo, or alkoxylcarbonyl groups; or R" and R" are both lower alkyl groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
  • the invention includes a compound where at least one of Y and Z is an amino group.
  • the invention includes where Y is amino and R 2 and Z are both hydrogen, then R 1 is other than a lower alkyl group
  • R 1 is independently selected from the group consisting of hydroxy (lower) alkyl, acetoxy(lower)alkyl, lower acyloxy(lower)alkyl, lower alkyl;
  • R 2 is independently selected from the group consisting of hydroxy (lower) alkyl, acetoxy(lower)alkyl, lower acyloxy(lower)alkyl, lower alkyl, or R 1 and R 2 together with their ring carbons may be an aromatic fused ring;
  • Z is hydrogen or an amino group
  • Y is an alkynylmethyl group, or a group of the formula
  • R" wherein R" is hydrogen and R'" is a lower alkyl group, optionally substituted by an aryl group, or an aryl group, the aryl group optionally substituted by one or more lower alkyl, halo, or alkoxylcarbonyl groups; or R" and R'" are both lower alkyl groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.
  • R 1 and R 2 are methyl; Z is hydrogen; Y is a group of the formula:
  • R is selected from hydrogen, C ]-6 linear or branched alkyl and cycloalkyl; or together with their ring carbons form a C 5 -C 7 fused cycloalkyl ring having up to two double bonds including any fused double bond of the -olium containing ring, which cycloalkyl ring is optionally substituted by one or more substituents selected from alkyl and fluoro;
  • R 2 is selected from hydrogen, C 1-6 linear or branched alkyl and cycloalkyl; or together with their ring carbons form a C 5 -C 7 fused cycloalkyl ring having up to two double bonds including any fused double bond of the -olium containing ring, which cycloalkyl ring is optionally substituted by one or more substituents selected from alkyl and fluoro;
  • Z is hydrogen or C r6 linear or branched alkyl;
  • Y is a group of the formula -CH(R )-C(O)-R wherein
  • R is hydrogen, C 1-6 linear- or branched- alkyl, or cycloalkyl
  • R is a C 6 or C 10 aryl, wherein R is optionally substituted with one or more substituents selected from the group consisting of alkyl and halo;
  • Q is S; and X is a pharmaceutically acceptable anion.
  • the above compounds are capable of inhibiting the formation of advanced glycosylation endproducts on target molecules, including, for instance, proteins, as well as being capable of breaking or reversing already formed advanced glycosylation endproducts on such proteins.
  • the compounds employed in accordance with this invention inhibit this late-stage Maillard effect and reduce the level of the advanced glycosylation endproducts already present in the protein material.
  • the rationale of the present invention is to use compounds which block, as well as possibly reverse, the post-glycosylation step, e.g., the formation of fluorescent chromophores and cross-links, the presence of which may be associated with, and leads to diseases such as types I and type II diabetes, metabolic syndrome, and/or insulin resistance.
  • the compound would prevent the formation of such chromophores and of cross-links between protein strands and trapping of proteins onto other proteins and reverse the level of such cross-link formation already present.
  • the chemical nature of the early glycosylation products with which the compounds of the present invention are believed to react may vary, and accordingly the term "early glycosylation product(s)" as used herein is intended to include any and all such variations within its scope.
  • early glycosylation products with carbonyl moieties that are involved in the formation of advanced glycosylation endproducts, and that may be blocked by reaction with the compounds of the present invention have been postulated.
  • the early glycosylation product may comprise the reactive carbonyl moieties of Amadori products or their further condensation, dehydration and/or rearrangement products, which may condense to form advanced glycosylation endproducts.
  • reactive carbonyl compounds containing one or more carbonyl moieties (such as glycolaldehyde, glyceraldehyde or 3-deoxyglucosone) may form from the cleavage of Amadori or other early glycosylation endproducts, and by subsequent reactions with an amine or Amadori product, may form carbonyl containing advanced glycosylation products such as alkylformyl-glycosylpyrroles.
  • carbonyl moieties such as glycolaldehyde, glyceraldehyde or 3-deoxyglucosone
  • EbIe et al. thereby observed that cross-linking continued to occur not only with the glycosylated protein but with non-glycosylated proteins as well.
  • One of the observations noted by EbIe et al. was that the reaction between glycosylated protein and the protein material appeared to occur at the location on the amino acid side chain of the protein. Confirmatory experimentation conducted by EbIe et al. in this connection demonstrated that free lysine would compete with the lysine on RNase for the binding of glycosylated protein.
  • An AP-dione with the structure of an amino- 1,4-dideoxyosone has been isolated by trapping model APs with the AGE-inhibitor aminoguanidine. Subsequent elimination of the 5-hydroxyl gives a l,4,5-trideoxy-l-alkylamino-2, 3-hexulos-4- ene (AP-ene-dione) (III), which has been isolated as a triacetyl derivative of its 1,2-enol form.
  • Amadori-diones particularly the AP-ene-dione, would be expected to be highly reactive toward protein cross linking reactions by serving as targets for the addition of the amine (Lys, His)-, or sulfhydryl (Cys)-based nucleophiles that exist in proteins, thereby producing stable cross links of the form (IV).
  • linear AP-ene-dione of (III) and the stable 20 cross-link of (IV) may cyclize to form either 5- or 6-member lactol rings, although only the 6-member cyclic variant is shown in Scheme A set forth above.
  • AGE-crosslinks that form under experimental conditions consist of an ⁇ -diketone or related structure that is susceptible to cleavage by the advantageous bidentate-type molecules of the compounds of formula I under physiological conditions.
  • the present invention likewise relates to methods for inhibiting the formation of advanced glycosylation endproducts, and reversing the level of already formed advanced glycosylation endproducts, which comprise contacting the target molecules with a composition of the present invention.
  • the present methods and compositions hold the promise for arresting, and to some extent reversing, the aging of key proteins both in animals and plants, and concomitantly, conferring both economic and medical benefits as a result thereof.
  • the therapeutic implications of the present invention relate to the a method of treating or preventing diseases such as types I and II diabetes, metabolic syndrome, and insulin resistance.
  • the present invention relates to a method of treating or preventing complications that arise from a reduction in nNOS expression.
  • the present invention relates to a method of treating or preventing diseases such as types I and II diabetes, metabolic syndrome, and insulin resistance.
  • compositions of the present invention are utilized for in vivo or therapeutic purposes (e.g., acute or prophylactic treatment), it may be noted that the compounds used therein are biocompatible.
  • Pharmaceutical compositions may be prepared with a therapeutically effective quantity of the compounds of the present invention and may include a pharmaceutically acceptable carrier, selected from known materials utilized for this purpose. Such compositions may be prepared in a variety of forms, depending on the method of administration. Also, various pharmaceutically acceptable addition salts of the compounds of the invention may be utilized.
  • a liquid form would be utilized in the instance where administration is by intravenous, intramuscular or intraperitoneal injection.
  • solid dosage forms such as tablets, capsules, or liquid dosage formulations such as solutions and suspensions, etc.
  • a solution, a lotion or ointment may be formulated with the agent in a suitable vehicle such as water, ethanol, propylene glycol, perhaps including a carrier to aid in penetration into the skin or eye.
  • a topical preparation could include up to about 10% of the compound of the invention.
  • Other suitable forms for administration to other body tissues are also contemplated.
  • the animal host intended for treatment may have administered to it a quantity of one or more of the compounds, in a suitable pharmaceutical form.
  • Administration may be accomplished by known techniques, such as oral, topical and parenteral techniques such as intradermal, subcutaneous, intravenous or intraperitoneal injection, as well as by other conventional means. Administration of the compounds may take place over an extended period of time.
  • the compound of the invention is formulated in compositions in an amount effective to inhibit and reverse the formation of advanced glycosylation endproducts.
  • the compound of the invention is formulated in compositions in an amount effective to inhibit the expression of intestinal neuronal nitric oxide synthase nNOS. This amount will, of course, vary with the particular agent being utilized and the particular dosage form, but typically is in the range of 0.01% to 1.0%, by weight, of the particular formulation.
  • the compounds encompassed by the invention are conveniently prepared by chemical syntheses well-known in the art. Certain of the compounds encompassed by the invention are well-known compounds readily available from chemical supply houses and/or are prepared by synthetic methods specifically published therefor. For instance, 3,4-dimethyl-5-(2- hydroxyethyl) thiazolium iodide; 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide; 3- benzyl-5-(2-hydroxyethyl) -4-methylthiazolium chloride; and 3-(carboxymethyl) benzothiazolium bromide are obtainable from compounds described in the chemical and patent literature or directly prepared by methods described therein and encompassed by the present invention are those such as 3-(2-phenyl-2-oxoethyl)-4-methylthiazolium bromide and 3-benzyl-5- (2-hydroxyethyl) -4-methyl thiazolium chloride [Potts et al., J
  • the AGEs/ALEs, N ⁇ (carboxymethyl)lysine (CML) and N ⁇ (carboxyethyl)lysine (CEL) were quantified by isotope dilution, selected ion monitoring gas chromatography-mass spectrometry (SIM- GC/MS) [Dyer, D.G. et al. Accumulation of Maillard reaction products in skin collagen in diabetes and aging. J Clin Invest 91, 2463-9 (1993)] and normalised to their parent amino acid lysine. Pentosidine was analysed by RP-HPLC and was also normalised to lysine content [Dyer, D.G. et al. Accumulation of Maillard reaction products in skin collagen in diabetes and aging. J Clin Invest 91, 2463-9 (1993)].
  • Dietary CML levels were determined by in house ELISA. ELISA in clear supematants obtained from rodent food following powdering in a mortar and pestle and overnight extraction.
  • MIN6N8 cells SV40 transformed insulinoma cells derived from non-obese diabetic (NOD) mice [Miyazaki, J. et al. Establishment of a pancreatic beta cell line that retains glucose-inducible insulin secretion: special reference to expression of glucose transporter isoforms. Endocrinology 127, 126-32 (1990)], were grown in Dulbecco's modified eagle's medium containing 15% fetal bovine serum, 2mmol/L glutamine and penicillin-streptomycin with normal glucose (5mmol/L) or high glucose.
  • AGE-BSA AGE-BSA
  • BSA BSA- lOO ⁇ g/mL
  • MIN6 cells were seeded in 12-well plates and treated for 7d. Cells were washed once with modified Krebs-Ringer Bicarbonate HEPES buffer (KRBH; 110.8mM NaCl, 4.87mM KCL, 2.29mM CaCl 2 .2H 2 O, 1.22mM KH 2 PO 4 , 1.2ImM MgSO 4 .7H 2 O, 25.7mM NaHCO 3 , 10.4mM HEPES, 0.1% BSA) containing 2.8mM glucose and pre-incubated with the same buffer for 30mins at 37°C.
  • modified Krebs-Ringer Bicarbonate HEPES buffer KRBH; 110.8mM NaCl, 4.87mM KCL, 2.29mM CaCl 2 .2H 2 O, 1.22mM KH 2 PO 4 , 1.2ImM MgSO 4 .7H 2 O, 25.7mM NaHCO 3 , 10.4mM HEPES, 0.1% BSA
  • MIN6 cells were loaded with ImM serotonin (5-hydroxtryptamine) for 16 hours before the glucose challenge as described above.
  • the incubation buffer was collected and assayed for 5-HT by competitive serotonin EIA.
  • Glucose uptake was determined using 3 H-2-deoxy-glucose ( 3 H-2-DG). Non-specific uptake was assessed using cytochalasin-B, which was subtracted from total uptake.
  • Cells were serum deprived for 4hrs, washed twice in warm phosphate buffered saline (PBS) containing 0.1% w/v bovine serum albumin (BSA) and incubated for 30mins at 37°C. Following this, cell treatments; insulin (10OnM), phenformin (ImM), HDL (50mg/ml), apoAI (40mg/ml) and cytochalasin-B (1OmM) were added to the PBS/BSA solution and incubated for lhr.
  • PBS phosphate buffered saline
  • BSA bovine serum albumin
  • MIN6 cells were plated onto 6 well plates at a density of 2 x 10 5 cells/well in complete growth medium (10% fetal calf serum, 1% L-glutamine, 1% penicillin/streptomycin antibiotic and 25mM D-glucose) to reach 30-40% confluency on the day of transfection.
  • complete growth medium 10% fetal calf serum, 1% L-glutamine, 1% penicillin/streptomycin antibiotic and 25mM D-glucose
  • UCP-2 gene silencing with siRNA UCP-2 gene silencing was performed using a siRNA target sequence. Using this sequence the siRNA was then constructed using a SilencerTM siRNA Construction Kit. The cell transfection conditions were similar to those utilised for RAGE except that the siRNA transfection was performed using TKO reagent, and 4nM of UCP-2 siRNA where 50% inhibition of UCP-2 expression was evident at a 2:1 ratio of TKO: siRNA. A concentration dependent inhibition from (2-12nM) was confirmed by real time RT-PCR and protein immunoblotting for UCP-2 (data not shown). Transfection efficency of siRNA was determined using fluorescence. MIN6N8 A TP production
  • KRBB pre-warmed Krebs-Ringer Bicarbonate buffer
  • the 340 (Ca 2+ -bound chelator), 380 (Ca 2+ -free), and 340/380nm ratio signals were recorded continuously over a period of 300s with CCD video camera.
  • the intracellular Ca 2+ concentration ([Ca 2+ ],) is expressed as the 340/380nm ratio.
  • the calcium channel blocker, verapamil was used as a control.
  • Glycohemoglobin measured by automated affinity HPLC correlates with both short-term and long-term antecedent glycemia.
  • Clin Chem 40, 1317-21. (1994)] were measured each month. Animals were culled by exsanguination at 1 or 4 months. Administration of diets high in AGE content to healthy rodents
  • a seven point standard curve was constructed using AGE-BSA.
  • sample diluted at 1/10, 000 to 1/20, 000
  • 50 mM carbonate buffer pH 9.6
  • PBS phosphate-buffered saline
  • Tween-20 0.1% Tween-20
  • the bile duct was cannulated and injected with 10ml of cold Hanks balanced salt solution (HBBS) containing 0.75mg/ml collagenase type V.
  • HBBS Hanks balanced salt solution
  • the pancreas was then incubated at 37 0 C in a shaking water bath for 10-20 mins. Once the digestion was complete, the pancreas was disrupted by vigorous shaking and filtered through 500 ⁇ m mesh.
  • the pancreatic islets were separated from exocrine tissue by histopaque density gradient, which the islets were suspended in histopaque 1.119g/l, followed by layering of histopaque 1.083g/l and histopaque 1.077g/l (Sigma). The hand-picked islets were then rested overnight and RNA extracted as below.
  • RNA extracted from pancreatic tissue collected immediately into RNA later or from MIN 6 cells were used to synthesize cDNA with the Superscript First strand synthesis system for RT-PCR.
  • Gene expression for each of the sequences listed below were analysed by real-time quantitative RT-PCR performed with the TaqMan system based on real-time detection of accumulated fluorescence [Candido, R. et al. A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes. Circ Res 92, 785-92 (2003)].
  • the forward primer was 5'-TGGTTCTCACTTGGTGGAAGCT-S' (SEQ ID NO: 1)
  • the reverse primer 5'-GGACATGGGTGTGTAGAAGAATCC-S'
  • the probe was 6-FAM CCCACACACCAGGTAG-MGB (SEQ ID NO: 3)
  • the probe was as for rat, however the forward primer was 5 'TC AAGCAGC ACCTTTGTGGTT- 3 ' (SEQ ID NO: 4) and the reverse primer 5 ' -GGGAC ATGGGTGTGTAGAAGAAG-3 ' (SEQ ID NO: 5). Fluorescence for each cycle was quantitatively analysed.
  • Tissue sections were consecutively stained with biotinylated IgG for 10 mins and avidin-biotin horseradish peroxidase complex for 15 mins before a substrate solution of 3,3'-diaminobenzidine tetrahydrochloride was added. Sections were counterstained in Harris' haematoxylin and mounted in dePex. Negative control sections had the omission of the primary antibody. Positive control tissues were also included.
  • DNA fragmentation is a hallmark of cells where endonucleases have been activated during the process of cell death.
  • Cell death was identified by 3' in situ end labelling of fragmented DNA with biotinylated deoxyuridine-triphosphate. Terminal transferase labels the nicked DNA with labelled deoxy-uridine-triphosphate (dUTP), which is subsequently detected by immunohistochemical techniques as above. Sections of formalin fixed tissue were dewaxed and hydrated.
  • the aim of the following examples was to determine if AGEs, directly contribute to insulin secretory defects, independent to hyperglycaemia.
  • the insulinoma cell line MIN6N8 cells (derived from a ⁇ cell insulinoma) were exposed to AGEs and mitochondrial function, Ca 2+ flux and insulin secretion assessed.
  • the effects of strategies to reduce AGE accumulation, block AGE signalling via RAGE with the antagonist of AGE-RAGE interactions, soluble RAGE and gene silencing with UCP-2 siRNA were also determined on GSIS.
  • AGE formation requires amino groups on proteins.
  • albumin was used as representative example of a circulating AGE modified protein present in vivo. Endotoxin levels within all preparations were found to be below assay detectable levels ( ⁇ 2.5EU/ml).
  • Analysis of the principal AGE modifications of lysine residues revealed that the major moiety in both AGE-RSA (rat serum albumin) and AGE-BSA (bovine serum albumin) was carboxymethyllysine (CML; 38.2 ⁇ 3.6 and 67.0+1.2 mmol/mol lysine respectively), although pentosidine (0.0037 and 0.0029 mmol/mol lysine) and carboxyethyllysine (CEL; 1.2 ⁇ 0.2 and 1.4 ⁇ 0.2 mmol/mol lysine) were also detected.
  • CML carboxymethyllysine
  • pentosidine 0.0037 and 0.0029 mmol/mol lysine
  • CEL carboxyethyllysine
  • Exposure ofMIN6N8 cells to AGEs causes insulin secretory defects independent to glucose concentrations in a time dependent manner.
  • MIN6N8 cells demonstrated basal hypersecretion of insulin, which was attenuated by treatment with the AGE cross-link breaker alagebrium (ALT; Fig Ia). There were modest changes in basal insulin secretion noted in normal glucose (NG; 5mmol/L) at 7 days
  • Alagebrium is also referred to as alagebrium chloride, ALT-711 or 3-(2-phenyl-2-oxoethyl)-4,5- dimethylthiazolium chloride. These terms are used interchangeably throughout.
  • Glucose stimulated insulin secretion for cells grown in high glucose conditions was elevated as compared to cells grown in normal glucose at day 7 (Fig Ib).
  • Proinsulin gene expression in MIN6N8 cells at 7 days was unchanged by high glucose, however, concomitant AGE exposure in high glucose media markedly decreased its expression (Cont HG-0.86 ⁇ 0.11 vs HG AGE-BSA-0.28 ⁇ 0.05, PO.001) and this decrease was attenuated with alagebrium treatment (HG AGE-BSA vs HG AGE-BSA+ALT- 2.30 ⁇ 0.52; P ⁇ 0.001). There was also a significant decrease in proinsulin gene expression seen with AGE exposure under normal glucose conditions at day 7 (Cont NG-1.02 ⁇ 0.11 vs NG AGE-BSA- 0.51 ⁇ 0.09; P ⁇ 0.05).
  • RAGE had increases in both the gene and surface expression of human RAGE.
  • pRAGE transfected cells showed a decrease in GSIS, which was also consistent with that seen with AGE-BSA treatment (Fig Ie).
  • sRAGE soluble RAGE
  • Figure 1 For Figures Ia-Ic, cells were exposed to either 25mM glucose (HG) for 7 days or 5mM glucose (NG) for 28 days in the presence and absence of AGE-BSA (lOO ⁇ g/ml). White bars - Glucose only, Black Bars - Glucose and AGE-BSA, Grey bars - Glucose and BSA, Checked bars - Glucose, AGE-BSA and the AGE inhibitor, alagebrium, (ALT - 1 ⁇ M). a) Basal insulin secretion, b) 2OmM glucose stimulated insulin secretion (GSIS). c) Flow cytometry analysis for cell surface RAGE.
  • MIN6N8 cells were transiently transfected with human full length RAGE or the control vector pCIneo, for 7 days in 25mM glucose (80% transfection efficiency determined by co-transfection with SEAP).
  • EXAMPLE 3 AGEs disrupt glucose stimulated insulin secretion via by uncoupling, interruption of ATP production and Ca H flux resulting in mitochondrial superoxide production.
  • Transection reagent (TKO) alone nor UCP-2 siRNA in the absence of TKO did not affect GSIS (Fig 2e).
  • Figure 2 MIN6N8 cells were exposed to 25mM glucose (HG) for 7 days in the presence and absence of AGE-BSA (lOO ⁇ g/ml).
  • Table 1 Rodent physiological and metabolic parameters following AGE-RSA infusion . Plasma glucose and glycated haemoglobin are included as measures of glycaemic control at the study endpoints (1 or 4 months). Final body weight and plasma CML (AGE) levels are also shown.
  • the number of proliferating ⁇ cells within islets was assessed using PCNA immunohistochemistry. At 1 month, there was a significant increase in the number of ⁇ cells proliferating cells within islets from animals which received AGE-RSA, as compared to both Sham and RSA groups (Fig 3 c). Confirmation of ⁇ cells as the proliferating cell type, was performed by concomitant immunostaining with insulin.
  • Gene expression of proinsulin was significantly decreased by AGE-RSA infusion as compared to the sham and RSA treated groups (Fig 4b). Changes in insulin AUC, incremental first phase insulin secretion and pancreatic islet insulin expression seen with AGE-RSA, were each attenuated by treatment with alagebrium (Fig 4a-b).
  • Figure 4 20mg/kg/day AGE-RSA or RSA was administered for 4 months in the presence and absence of the AGE cross-link breaker alagebrium (ALT, lOmg/kg/day) to 8 week old male Sprague Dawley rats. Sham-closed triangles; AGE-RSA-Open squares; RSA- Closed circles; AGE-RSA+ALT-Open circles, a) Insulin levels before and during i.v. glucose challenge (lg/kg). b) Real time RT-PCR for the gene expression of proinsulin in pancreata.
  • AGE cross-link breaker alagebrium ALT, lOmg/kg/day
  • a high dietary intake of AGEs causes insulin deficiency, secretory defects and hyperglycaemia.
  • Circulating levels of CML were significantly increased in rats consuming both the High AGE (1246.0 ⁇ 284.3 nmol/mol lysine vs low AGE 523.0 ⁇ 74.8, p ⁇ 0.05) and High Dextrose containing diets (806.2 ⁇ 125.2 nmol/mol lysine, p ⁇ 0.05 vs low AGE).
  • Figure 5 Groups of healthy SD rats were administered isocaloric diets, which differed only in AGE (High and Low AGE) or glucose content (High Dext) for 6 months, a) Fasting plasma insulin and glucose levels at 6 months, b) Insulin levels before and during i.v glucose challenge, c) Proinsulin Gene expression by real time RT-PCR. d) Islet RAGE expression by immunohistochemistry. e) Islet AGE (CML) content by immunohistochemistry. *p ⁇ 0.05 vs Low AGE fed group, fp ⁇ .001 vs Low AGE, Jp ⁇ 0.01 vs Low AGE.
  • MIN6N8 cells were treated for 7 days in High Glucose (25mmol/L glucose) with either lOOug/ml AGE-BSA or BSA. Six replicates for each group were completed. Prior to commencement of insulin secretion testing at day 7, different groups were incubated with lumol/L alagebrium chloride (ALT-711) for varying times to complete the following groups:
  • BSA control group (ii) AGE-BSA + ALT-711 for 30 mins before insulin secretory testing, (iv) AGE-BSA + ALT-711 for 60 mins before insulin secretory testing, (v) AGE-BSA + ALT-711 for 2 hours before insulin secretory testing, (vi) AGE-BSA + ALT-711 for 4 hours before insulin secretory testing.
  • Acute insulin secretion involved transferring cells to 3mmol/L glucose to take basal insulin secretion. The cells were then challenged with 20mmol/L glucose (acute secretion is 1 st 20 mins in culture), and media collected for 1 hour. Insulin secretion during the various phases is expressed as % content (which includes intracellular insulin as well).
  • Figure 7 Insulin secretory function of MIN6N8 cells exposed to AGE-BSA at day 7 expressed as a % of total content.
  • Figure 7A Basal insulin secretion.
  • Figure 7B Acute insulin secretion.
  • Figure 7C Total insulin secretion.
  • Figure 7D Intracellular insulin content. *p ⁇ 0.05 vs AGE-BSA (AGE), #p ⁇ 0.01 vs AGE-BSA (AGE).
  • FIG 8 A IPGTT graph: Plasma insulin concentrations over time following an intraperitoneal bolus of glucose given at 16 weeks.
  • LAGE group are wild type (C57BL/6J) mice which have been fed a control diet low in AGE content (LAGE) and followed for 16 weeks.
  • HFAT+HAGE is a western style diet which is isocalorically identical to the LAGE diet except for fat and AGE content.
  • Two groups were fed this diet for 16 weeks , namely wild type (C57BL/6J) and RAGE deficient (RAGE-/-) mice.
  • a fourth group of wild type mice were fed the western (HFAT+HAGE) diet for 16 weeks and were concomitantly administered alagebrium (ALT-711; lmg/kg/day oral gavage).
  • Insulin This is a ratio of the area under the curve of plasma insulin and glucose during the IPGTT testing. The higher the ratio of insulin to glucose in this test, the more insulin resistance is present.
  • the groups are as above. Simplistically, it is clear however that there is insulin resistance in both the groups fed the western diet ie RAGE-/- mice are not protected against the devleopment of IR. Alagebrium therapy ameliorated the effects seen with the western diet in the wild type mice.
  • FIG. 8C Fasting plasma data: These values are measured following a 6 hour fast (equivalent to overnight for mice). Again it is obvious that mice fed a western style diet have poor glycaemic control with elevated fasting plasma glucose and insulin levels. The data is significant for the western diets in both strains compared to the LAGE group (p ⁇ 0.01 vs LAGE). Alagebrium treatment also normalised plasma insulin and glucose (significant compared to western diet group p ⁇ 0.05).
  • Figure 8 Intraperitoneal glucose tolerance testing in mice.
  • Figure 8A Plasma insulin curve over time
  • Figure 8B AUC insulin to AUC glucose ratio
  • Figure 8C Fasting plasma glucose and insulin data.
  • Advanced glycation endproducts are unavoidable byproducts of various metabolic pathways, such as glucose metabolism. They are formed by reactive metabolic intermediates such as methylglyoxal (MG). These reactive intermediates bind to proteins, DNA, and other molecules and disrupt their structures and functions, which leads to different diseases such as vascular complications of diabetes, atherosclerosis, hypertension, and aging. Plasma MG levels are elevated in diabetes. The effects of exogenous MG have been studied using very high doses in most in vivo and in vitro studies. Alagebrium was tested for its ability to inhibit MG, inhibit MG-induced AGE formation and assess its ability to treat or prevent disorders related to insulin resistance such as diabetes and hypertension.
  • MG methylglyoxal
  • the acute effects of a single intraperitoneal low dose (8.64 mg/kg) of MG were analysed in Sprague-Dawley rats. MG levels were measured by HPLC. An intravenous glucose tolerance test (IVGTT) was preformed 2 h after the administration of MG. Endothelium-dependent relaxation was tested in aortic rings. Plasma MG levels peaked 15 min after i.p. injection (2.50 ⁇ 0.20 ⁇ M vs. 1.60 ⁇ 0.18 ⁇ M control) and were significantly decreased (1.86 ⁇ 0.04 ⁇ M) after co-administration of alagebrium. The IVGTT area under curve for glucose was significantly greater after MG [4277 ⁇ 270 vs.
  • Methylglyoxal is a highly reactive dicarbonyl compound that induces oxidative stress in vascular smooth muscle cells (A-10 cells). Since mitochondria are considered the most important source of free radical generation, the effect of MG on mitochondria of A-10 cells was investigated. Additionally, alagebrium was tested for its ability to inhibit the resultant effects of MG on mitochondria.
  • Mitochondria were prepared from A- 10 cells by lysis with the detergent, followed by low (600 ⁇ g) and high speed (1 l,000 ⁇ g) centrifugation. MG was measured by HPLC. Reactive oxygen species (ROS) and superoxide were detected by molecular probes and read under confocal microscopy. Nitrotyrosine (a marker for peroxynitrite formation), MG- induced advance glycation endproduct (AGE), N 6 -(carboxyethyl) lysine (CEL), and mnSOD were measured by immunostaining.
  • ROS Reactive oxygen species
  • Nitrotyrosine a marker for peroxynitrite formation
  • AGE MG- induced advance glycation endproduct
  • CEL N 6 -(carboxyethyl) lysine
  • mnSOD were measured by immunostaining.
  • MG levels in mitochondria were significantly increased along with increased production of ROS compared to control.
  • Alagebrium, antioxidant n-acetyl-cysteine ( ⁇ AC), and peroxynitrite scavenger uric acid reversed the effects of MG.
  • MG treatment significantly increased nitrotyrosine, which was decreased by co-treatment with alagebrium or ⁇ AC.
  • Increased production of superoxide in mitochondria of MG treated cells was reduced by the co-application of alagebrium or superoxide dismutase (SOD) mimetic 4-hydroxy-tempo.
  • SOD superoxide dismutase

Landscapes

  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés de thiazolium pour le traitement d'un patient souffrant d'un trouble métabolique lié à une résistance à l'insuline et/ou à un dysfonctionnement des cellules bêta, y compris des patients souffrant d'un diabète de type I, d'un diabète de type II, d'un syndrome métabolique et/ou d'un prédiabète.
PCT/US2008/011886 2007-10-18 2008-10-17 Composés de thiazolium destinés au traitement ou à la prévention de maladies associées à une résistance à l'insuline WO2009051804A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US99958307P 2007-10-18 2007-10-18
US60/999,583 2007-10-18
US7030608P 2008-03-21 2008-03-21
US61/070,306 2008-03-21

Publications (1)

Publication Number Publication Date
WO2009051804A1 true WO2009051804A1 (fr) 2009-04-23

Family

ID=40260617

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/011886 WO2009051804A1 (fr) 2007-10-18 2008-10-17 Composés de thiazolium destinés au traitement ou à la prévention de maladies associées à une résistance à l'insuline

Country Status (1)

Country Link
WO (1) WO2009051804A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9353078B2 (en) 2013-10-01 2016-05-31 New York University Amino, amido and heterocyclic compounds as modulators of rage activity and uses thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022095A2 (fr) * 1995-01-18 1996-07-25 Alteon Inc. Utilisation de composes de thiazolium pour empecher et inverser la formation de produits finis de glycosylation avancee
WO2001062250A1 (fr) * 2000-02-23 2001-08-30 Alteon, Inc. Composes de thiazolium et traitements de troubles lies au vieillissement des proteines
WO2002007725A1 (fr) * 2000-07-13 2002-01-31 Alteon, Inc. Procede de traitement des maladies fibreuses ou autres indications
WO2006032042A2 (fr) * 2004-09-15 2006-03-23 Regeneron Pharmaceuticals, Inc. Procedes pour traiter l'obesite au moyen d'agents therapeutiques
WO2007044309A2 (fr) * 2005-10-05 2007-04-19 Vasix Corporation Appareil et méthode pour inhiber la formation du complexe ptag
WO2008025870A1 (fr) * 2006-08-28 2008-03-06 Faron Pharmaceuticals Oy Compositions utiles en particulier dans le traitement ou la prévention du syndrome métabolique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022095A2 (fr) * 1995-01-18 1996-07-25 Alteon Inc. Utilisation de composes de thiazolium pour empecher et inverser la formation de produits finis de glycosylation avancee
WO2001062250A1 (fr) * 2000-02-23 2001-08-30 Alteon, Inc. Composes de thiazolium et traitements de troubles lies au vieillissement des proteines
WO2002007725A1 (fr) * 2000-07-13 2002-01-31 Alteon, Inc. Procede de traitement des maladies fibreuses ou autres indications
WO2006032042A2 (fr) * 2004-09-15 2006-03-23 Regeneron Pharmaceuticals, Inc. Procedes pour traiter l'obesite au moyen d'agents therapeutiques
WO2007044309A2 (fr) * 2005-10-05 2007-04-19 Vasix Corporation Appareil et méthode pour inhiber la formation du complexe ptag
WO2008025870A1 (fr) * 2006-08-28 2008-03-06 Faron Pharmaceuticals Oy Compositions utiles en particulier dans le traitement ou la prévention du syndrome métabolique

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
ASTON-MOURNEY KATHRYN ET AL: "Investigational agents that protect pancreatic islet beta-cells from failure.", EXPERT OPINION ON INVESTIGATIONAL DRUGS OCT 2005, vol. 14, no. 10, October 2005 (2005-10-01), pages 1241 - 1250, XP002511886, ISSN: 1744-7658 *
COOPER M E: "Importance of advanced glycation end products in diabetes-associated cardiovascular and renal disease", AMERICAN JOURNAL OF HYPERTENSION, ELSEVIER, vol. 17, no. 12, 1 December 2004 (2004-12-01), pages S31 - S38, XP004761220, ISSN: 0895-7061 *
COUGHLAN M T ET AL: "Role of the AGE crosslink breaker, alagebrium, as a renoprotective agent in diabetes", KIDNEY INTERNATIONAL 200708 GB, vol. 72, no. SUPPL. 106, August 2007 (2007-08-01), pages S54 - S60, XP002511884, ISSN: 0085-2538 1523-1755 *
FORBES JOSEPHINE M ET AL: "Advanced glycation end product interventions reduce diabetes-accelerated atherosclerosis", DIABETES, vol. 53, no. 7, July 2004 (2004-07-01), pages 1813 - 1823, XP002511885, ISSN: 0012-1797 *
SOLDATOS GEORGIA ET AL: "Advanced-glycation end products in insulin-resistant states.", CURRENT HYPERTENSION REPORTS APR 2005, vol. 7, no. 2, April 2005 (2005-04-01), pages 96 - 102, XP008100525, ISSN: 1522-6417 *
UNOKI HIROYUKI ET AL: "Possible participation of advanced glycation end products in the pathogenesis of obesity-associated insulin resistance", DIABETES, vol. 54, no. Suppl. 1, 2005, & 65TH ANNUAL MEETING OF THE AMERICAN-DIABETES-ASSOCIATION; SAN DIEGO, CA, USA; JUNE 10 -14, 2005, pages A431 - A432, XP008100599, ISSN: 0012-1797 *
WOLFFENBUTTEL B H R ET AL: "Breakers of advanced glycation end products restore large artery properties in experimental diabetes", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE, WASHINGTON, DC.; US, vol. 95, no. 8, 14 April 1998 (1998-04-14), pages 4630 - 4634, XP002268923, ISSN: 0027-8424 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9353078B2 (en) 2013-10-01 2016-05-31 New York University Amino, amido and heterocyclic compounds as modulators of rage activity and uses thereof
US9364472B2 (en) 2013-10-01 2016-06-14 New York University Amino, Amido and heterocyclic compounds as modulators of RAGE activity and uses thereof
US10265320B2 (en) 2013-10-01 2019-04-23 The Research Foundation For The State University Of New York Amino, amido and heterocyclic compounds as modulators of rage activity and uses thereof

Similar Documents

Publication Publication Date Title
Nangaku et al. Randomized clinical trial on the effect of bardoxolone methyl on GFR in diabetic kidney disease patients (TSUBAKI study)
JP6764906B2 (ja) ヒト脂肪組織萎縮症を処置するためのレプチンの使用および該処置のための素因決定方法
Zhao et al. Branched-chain amino acids exacerbate obesity-related hepatic glucose and lipid metabolic disorders via attenuating Akt2 signaling
Coughlan et al. Advanced glycation end products are direct modulators of β-cell function
Ojima et al. Empagliflozin, an inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs-receptor axis
Huebschmann et al. Diabetes and advanced glycoxidation end products
De Zeeuw et al. Rationale and trial design of bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes: the occurrence of renal events (BEACON)
Capozzi et al. The limited role of glucagon for ketogenesis during fasting or in response to SGLT2 inhibition
DeFronzo et al. Pleiotropic effects of thiazolidinediones: implications for the treatment of patients with type 2 diabetes mellitus
Camici et al. Obesity-related glomerulopathy and podocyte injury: a mini review
CA2441834C (fr) Modulation d'un profile lipidique
AU2002359288A1 (en) Use of leptin for treating human lipoatrophy and method of determining predisposition to said treatment
Sharma et al. Structural and functional consequences of streptozotocin-induced diabetes on the kidney
JP2007020569A (ja) 糖尿病モデル
Redon Hypertension and the metabolic syndrome
WO2009051804A1 (fr) Composés de thiazolium destinés au traitement ou à la prévention de maladies associées à une résistance à l'insuline
WO2000066101A2 (fr) Procede permettant d'inhiber la formation d'un produit de glycation
US8580854B2 (en) Methods of suppression of rage gene expression and rage triggered inflammatory genes by selected age-inhibitors
Sanchez-Siles et al. Administration of PPARβ/δ agonist reduces copper-induced liver damage in mice: possible implications in clinical practice
Alicic et al. Diabetes Mellitus:: Management of Hypertension in Diabetes
Ahmadi et al. Gender effects on insulin resistance
Afzal et al. Adiponectin versus thiazolidinediones and angiotensin receptor blockers
Clapham Nicholas C. Turner Nicholas C. Turner received his PhD from the Uni-versity of London in 1982. He joined SmithKline Beecham in 1991 as Senior Pharmacologist. His research interests include the molecular and
Pajvani Functional consequences of adiponectin oligomerization state: The role of adiponectin in maintaining systemic insulin sensitivity

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08838962

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08838962

Country of ref document: EP

Kind code of ref document: A1