Nonpeptide insulin receptor agonists

Abstract

Modulation of the activity of the insulin receptor, enhancement of glucose uptake by cells, and other effects significant in the control and management of diabetes are accomplished using compounds of the formula whereineach A is independently a proton-accepting substituent;each R is independently a noninterfering substituent;n is 0, 1, or 2; andeach linker is independently an isostere of —NHCONH— or of —N═N— or of —NHCO—.Compounds in the genus of Formula (1) can also be used for structure activity studies to identify features responsible for the relevant activities.

Description

TECNICAL FIELD[0001]The invention relates to the substitution of nonpeptide compounds for peptide ligands that activate hormone receptors. More specifically, it concerns simple nonpeptide compounds that behave as agonists for the insulin receptor and enhance the effect of insulin on this receptor.BACKGROUND ART[0002]Among the many functions performed by peptides and proteins in metabolism is the ability to stimulate receptors at cell surfaces to effect intracellular consequences important in maintenance and development of the organism. Peptide and protein hormones interact with receptors specific for them so that the activity of the hormone is felt on designated cells exhibiting these receptors. The insulin receptor is present on virtually all cells and at high concentrations on the cells of the liver, skeletal muscles, and adipose tissue. Stimulation of the insulin receptor with insulin is an essential element in carbohydrate metabolism and storage.[0003]Diabetics either lack suffi...

AI Technical Summary

Benefits of technology

[0079]Mice which are standard models of Type II diabetes, db / db mice, were administered TER16998 at 10 mg / kg and 40 mg / kg, or a vehicle as a control. FIG. 8 shows the effect of this compound on the concentration of glucose in the blood of these animals. As shown in FIG. 8, 10 mg / kg to some extent and 40 mg / kg to an appreciable extent decrease blood glucose over a period of 24 hours from the time of administration.

[0080]Compounds TER17004 and TER17005, shown in FIG. 2E, replace certain azo-linkers of TER3935 with the corresponding amide linkers. These compounds are synthesized as shown in FIG. 9.

Problems solved by technology

While the recombinant production of insulin permits a less immunogenic form to be provided and assures a reliable supply of needed quantities, the necessity to administer the hormone by injection remains, due to the instability of peptides and proteins in the digestive tract.

However, to date, nonpeptide substances which can exert the effect of insulin on its receptor have eluded discovery.

However, the complete mechanism is still unresolved.

In any event, it has not as yet been possible to utilize simple molecules to provide the effect of a peptide hormone by stimulating receptor activity independently of the peptide hormone binding site.

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