Pharmaceutical compositions and methods for treatment of insulin-resistance and diabetes mellitus using thiol protease inhibitors such as E-64.

The University of Texas System

Treatment of insulin resistance and type 2 diabetes mellitus with a thiol protease inhibitor

This invention provides novel assays for measuring the metabolic side-effects of antiretroviral protease inhibitors on the Glut4 glucose transporter. The invention also provides improved methods for developing antiretroviral protease drugs, particularly those used to fight HIV infection. The invention further provides novel models of insulin-resistant glucose transport disease states.

Washington University

Inhibitors of retroviral protease as inducers of reversible insulin resistance in vitro and in vivo

The invention provides compounds and methods for inhibiting proteases. One aspect of the invention features pro-soft inhibitors which react with an activating protease to release an active inhibitor moiety in proximity to a target protease. In certain instances, compounds inhibit proteasomes and/or post-proline cleaving enzymes (PPCE), such as dipeptidyl peptidase IV. The compounds of the invention provide a better therapeutic index, owing in part to reduced toxicity and/or improved specificity for the targeted protease. Another aspect of the invention provides for the use of the disclosed compounds for treating Type II diabetes, insulin resistance, glucose intolerance, hyperglycemia, hypoglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.

Bachovchin; William W.

Lai; Hung-sen

Wu; Wengen

Trustees of Tufts College

Soft protease inhibitors, and pro-soft forms thereof

Methods are disclosed for determining progression of a condition, onset of a condition, or efficacy of treatment of a condition characterized by an adipocyte imbalance in a patient. In addition, methods are disclosed of treating diabetes, abnormal adipocyte activity, and insulin resistance using monomeric, homodimeric, and heterodimeric forms of certain C-terminal fragments of adiponectin receptor. In addition, methods of treating abnormal adipocyte activity, treating metabolic syndrome, causing insulin secretion, increasing insulin levels, inhibiting insulin degradation enzyme, treating Alzheimer's disease, treating cardiovascular disease associated with adiponectin levels, inhibiting ADAM-17 enzyme, inhibiting a protease, treating a condition associated with TNF-alpha, and treating a condition associated with HER2-neu are disclosed. Compositions, dosage forms, and kits are also disclosed.

insulin resistance/protease

Treatment of insulin resistance and type 2 diabetes mellitus with a thiol protease inhibitor

Inhibitors of retroviral protease as inducers of reversible insulin resistance in vitro and in vivo

Soft protease inhibitors, and pro-soft forms thereof

Monomeric and dimeric forms of adiponectin receptor fragments and methods of use

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