Methionine aminopeptidase-2 inhibitors and methods of use thereof

Abstract

The present invention provides methods of parasitic infections, thymoma, and lymphoid malignancies in a subject by administering to the subject a therapeutically effective amount of one or more of the compounds of the invention.

Description

RELATED APPLICATION[0001]This application is a continuation of U.S. patent application Ser. No. 11 / 416,622, filed May 3, 2006, Issuing; which is a continuation of U.S. patent application Ser. No. 10 / 429,174, filed May 2, 2003, now U.S. Pat. No. 7,105,482, issued Sep. 12, 2006; which is a continuation-in-part of U.S. patent application Ser. No. 10 / 138,935, filed May 2, 2002, now U.S. Pat. No. 6,919,307, issued Jul. 19, 2005; which is a continuation-in-part of U.S. patent application Ser. No. 10 / 001,945, filed Nov. 1, 2001; now U.S. Pat. No. 7,084,108, issued Aug. 1, 2006; which is a continuation-in-part of U.S. patent application Ser. No. 09 / 972,772, filed Oct. 5, 2001, now U.S. Pat. No. 7,037,890, issued May 2, 2006; which is a continuation-in-part of U.S. patent application Ser. No. 09 / 704,251, filed Nov. 1, 2000, now U.S. Pat. No. 6,548,477, issued Apr. 15, 2003. The entire contents of each of the aforementioned applications and patents are hereby incorporated by reference in thei...

AI Technical Summary

Benefits of technology

The present invention provides angiogenesis inhibitor compounds that can be used to treat lymphoid malignancies, such as chronic lymphoid leukemia and lymphoma. These compounds have a core that inhibits methionine aminopeptidase 2 (MetAP-2), which is involved in the formation of new blood vessels. By linking the MetAP-2 inhibitory core to a peptide, the compounds are able to cross the blood brain barrier and target specific cells. The compounds have a superior pharmacokinetic profile and are less toxic. The patent also describes a method for treating lymphoid malignancies by administering a combination of a MetAP-2 inhibitor and a second therapy, such as a chemotherapy or vaccine.

Problems solved by technology

Lymphoma is a type of cancer that can occur when an error occurs in the way a lymphocyte is produced, resulting in an abnormal cell.

Autoimmune disorders also present a serious health issue in the United States.

However, all mechanisms have a risk of breakdown and occasionally the immune system turns on its host environment in an aggressive manner as to cause disease.

This breakdown leads to the copious production of autoreactive B cells producing autoantibodies and / or autoreactive T cells leading to destructive autoimmune disease.

Efforts to control the invertebrate vector (carrier, such as the mosquito) of these diseases is, in many cases, difficult as a result of pesticide resistance, concerns regarding environmental damage and lack of adequate infrastructure to apply existing vector control methods.

Unfortunately, most existing therapeutics are either incompletely effective or toxic to the human host.

In a number of cases, even safe and effective drugs are failing as a result of the selection and spread of drug resistant variants of the parasites.

However, the use of such inhibitors (e.g., TNP-470) may be limited by their rapid metabolic degradation, erratic blood levels, and by dose-limiting central nervous system (CNS) side effects.

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