Combination of FBPase Inhibitors and Insulin Sensitizers for the Treatment of Diabetes

Abstract

Pharmaceutical compositions containing an FBPase inhibitor and an insulin sensitizer are provided as well as methods for treating diabetes and diseases responding to increased glycemic control, an improvement in insulin sensitivity, a reduction in insulin levels, or an enhancement of insulin secretion.

Description

RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10 / 780,948, filed Feb. 17, 2004, which is a divisional of U.S. application Ser. No. 09 / 470,649, filed Dec. 22, 1999, now U.S. Pat. No. 6,756,360, which claims benefit of U.S. Provisional Application No. 60 / 114,718, filed Dec. 24, 1998 and which are incorporated by reference herein in their entirety.BACKGROUND OF THE INVENTION [0002] A combination therapy of an insulin sensitizer and an FBPase inhibitor is disclosed for the treatment of diabetes, and other diseases where the control of blood glucose levels or an improvement in insulin sensitivity, reduction in insulin levels or an enhancement of insulin secretion is beneficial. Compositions used in the therapy are also disclosed. BACKGROUND OF THE INVENTION [0003] Diabetes mellitus (or diabetes) is one of the most prevalent diseases in the world today. Diabetes patients have been divided into two classes, namely type I or insulin-dependent dia...

AI Technical Summary

Benefits of technology

[0019] The instant invention is a combination therapy and a composition for the treatment for diabetes and diseases responding to improved glycemic control or to improve peripheral insulin sensitivity. The therapy requires administration of a insulin sensitizer agent, e.g. PPAR γ agonist, RXR ligand, or another agent known to enhance insulin action and an FBPase inhibitor either together or at a different time such that improved glycemic control is achieved. In another aspect of the invention, the combined therapy results in decreases in hepatic glucose output beyond that observed for glucose lowering doses of the insulin sensitizer agent. Furthermore, the combined therapy can result in improvements in insulin resistance and / or insulin secretion beyond that observed for either agent alone. Yet another aspect of the invention is that a combination therapy achieves similar benefits as observed with one or the other therapies alone but at significantly lower doses.

[0020] The present invention relates to methods and compositions for treating an animal having NIDDM or a condition associated with insulin resistance by administering to the animal a composition containing a pharmaceutically effective amount of an agent that enhances insulin sensitivity and a pharmaceutically effective amount of an FBPase inhibitor. The compositions of this invention are adapted to cure, improve or prevent one or more symptoms of NIDDM. A preferred drug combination will have high potency and low toxicity.

[0021] Another object of the invention relates to methods and compositions for treating insulin-requiring NIDDM patients. The combination therapy decreases the insulin requirement and associated safety risks.

[0137] The term “pharmacodynamic half-life” refers to the time after administration of the drug or prodrug to observe a diminution of one half of the measured pharmacological response. Pharmacodynamic half-life is enhanced when the half-life is increased by preferably at least 50%.

[0143] Insulin sensitizers used in this invention are compounds that alter the body's response to endogenous or exogeneous insulin or insulin-like molecules. This response can include an improvement in whole-body glucose disposal, a reduction in hepatic glucose output, an increase in insulin-mediated glycogenesis, and other manifestations of improved peripheral insulin resistance. In some instances, the insulin sensitizers used in this invention may also lower circulating triglycerides and / or free fatty acids, may increase HDL cholesterol levels, may reduce hyperinsulinemia, or may improve the pancreatic insulin secretory response. Examples of insulin sensitizers include compounds that activate or are agonists of the PPARγ receptor, are ligands of RXR that activate transcriptional activity of the RXR:PPAR γ heterodimer, or are compounds that achieve enhanced insulin sensitivity through modulation of enzyme activities in cell signalling pathways associated with insulin receptor activation. Enzymes in the latter pathways include protein kinase C, tyrosine phosphatase, PI-3-kinase, MAP kinase, and others. The insulin sensitizers used in this invention have affinity for PPARγ1, PPARγ2, and / or other isoforms of the PPARγ family, and contain either a thiazolidinedione ring structures a modified thiazolidinedione ring structure, or have a structure that is unrelated to the thiazolidinediones (eg. the 3-aryl-2-alkoxy propanoic acids). The insulin sensitizers also include compounds with affinity for RXRα, RXRβ, RXRγ and / or other RXR receptor isoforms, and are either retinoids such as 9-cis-retinoic acid and its analogs, rexinoids such as (tetramethyltetrahydronaphthyl)carbonylbenzoic acid analogs, or are of other structural classes. Insulin sensitizers used in this invention typically exhibit activity in assays known to be useful for characterizing compounds that act as insulin sensitizers. The assays include but are not limited to: (a) PPARγ binding assays; (b) RXR or RXR-PPARγ activation assays (eg. co-transfection or cis-trans assays); (c) insulin signaling assays such as those measuring receptor or signaling protein phosphorylation / expression (d) adipocyte binding assays; (e) glucose uptake assays in adipocytes or L6 myocytes; (f) adipocyte differentiation assays using triglyceride accumulation, glucose oxidation, or fat / carbohydrate metabolism gene expression as indeces; (g) insulin secretion assays in beta cell islets or the perfused pancreas; (h) pancreatic islet histology assays; (i) in vivo glucose disposal assays; (j) whole body insulin sensitivity assays using the in vivo hyperinsulinemic-glucose clamp technique; (k) hepatic glucose output assays utilizing labeling or NMR techniques; and (l) antihyperglycemic and / or triglyceride / free fatty acid lowering activity in animal models of diabetes such as the KK, ob / ob, or db / db mouse or the ZDF rat.

Problems solved by technology

The combination therapy decreases the insulin requirement and associated safety risks.

Images