Title:  Method for determining whether a compound is an insulin receptor kinase activator

United States Patent:  6,528,037

Issued:  March 4, 2003

Inventors:  Manchem; Prasad V. V. S. V. (South San Francisco, CA); Lum; Robert T. (Palo Alto, CA); Schow; Steven R. (Redwood Shores, CA)

Assignee:  Telik, Inc. (South San Francisco, CA)

Appl. No.:  115595

Filed:  April 2, 2002

A method for determining whether a compound is an insulin receptor kinase activator.

DETAILED DESCRIPTION OF THE INVENTION

The method of the present invention is used to determine whether a compound is an insulin receptor kinase activator. It comprises administering a compound to a non-human mammal concurrently treated with an HIV protease inhibitor, administering glucose to the mammal, and measuring the increase in plasma insulin or plasma glucose in the mammal, wherein a reduced increase in plasma insulin or plasma glucose in the mammal compared to a comparable mammal that has been treated with the HIV protease inhibitor and administered the glucose, but not administered the compound, indicates that the compound is an insulin receptor kinase activator.

Concurrent treatment means that the compound is administered at the same time the HIV protease inhibitor is administered or, at least, that the compound is administered at some time when the glucose metabolism of the animal is impaired by the action of the HIV protease inhibitor.

The insulin receptor kinase activators found by the method of this invention can be used for the uses disclosed in the section "Background to The Invention" discussed above.

The method of this invention comprises concurrent administration of the compound to be tested and an effective amount of an HIV protease inhibitor, followed or accompanied by administration of an effective amount of glucose. The preferred route of administration is oral.

An effective amount of glucose is the amount that produces a readily measurable increase in blood glucose or insulin levels shortly after administration in a normal mammal of the species being used in the method. A suitable effective amount of glucose in the rat is about 2.5 g/Kg orally.

An effective amount of the HIV protease inhibitor is the amount that produces a readily measurable difference between the blood glucose or insulin level in a mammal that has been administered the HIV protease inhibitor and glucose relative to a comparable mammal that has been administered glucose alone. A suitable effective amount for indinavir sulfate in the rat is from about 75 mg/Kg to about 100 mg/Kg orally.

A person of ordinary skill in the art will have no difficulty, having regard to that skill and this disclosure, in determining suitable amounts of glucose and HIV protease inhibitor for different mammalian species and for different HIV protease inhibitors.

The compound to be tested is desirably administered in an amount that produces a readily measurable difference between the blood glucose or insulin level in a mammal that has been administered the HIV protease inhibitor, the compound, and glucose relative to a comparable mammal that has been administered the HIV protease inhibitor and glucose alone, especially an amount that produces blood glucose or insulin levels comparable to those of a comparable mammal administered glucose alone. Comparison of the amounts of a test compound with the amount of a known insulin receptor kinase receptor activator required to give the same blood glucose or insulin levels under the same test conditions will give an indication of the potency of the compound; and in this manner the method provides not just an indication of whether a compound is an insulin receptor kinase activator, but also how potent it is.

Claim 1 of 5 Claims

We claim:

1. A method for screening a compound to determine its activity as an insulin receptor kinase activator, comprising:

administering the compound to a non-human mammal concurrently treated with an HIV protease inhibitor;

administering glucose to the non-human mammal; and

measuring the level of plasma insulin or plasma glucose in the non-human mammal, where a reduced level of plasma insulin or plasma glucose in the non-human mammal compared to a comparable non-human mammal that has been treated with the HIV protease inhibitor and administered the glucose, but not administered the compound, indicates that the compound is an insulin receptor kinase activator.
 

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