Methionine aminopeptidase-2 inhibitors and methods of use thereof

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 their entirety.

Lymphoma is a leading cause of death in the United States. 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. These abnormal cells can accumulate by two mechanisms: (a) they can duplicate faster than normal cells, or (b) they can live longer than normal lymphocytes. Like normal lymphocytes, the cancerous lymphocytes can grow in many parts of the body, including the lymph nodes, spleen, bone marrow, blood, or other organs. There are two main types of cancer of the lymphatic system. One is called Hodgkin\'s disease, while the other is called non-Hodgkin\'s lymphoma.

Autoimmune disorders also present a serious health issue in the United States. A progressive and maintained response by the immune system against self-components is termed autoimmunity. Normally self-tolerance mechanisms prevent the immune response from acting on self-components. 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. The cellular mechanisms of autoimmunity are the same as those involved in beneficial immune responses to foreign components which include antibody-dependent cell cytotoxicity, delayed-type hypersensitivity (DTH), and T-cell lympholysis.

Human autoimmune diseases can be divided into two categories: organ-specific and systemic. In organ-specific autoimmune disease, autoreactivity is directed to antigens unique to a single organ. In systemic autoimmune disease, autoreactivity is largely directed toward a broad range of antigens and involves a number of tissues.

Disease in either type results from the generation of one or both autoreactive cell types (B or T cells). Autoreactive B cells lead to the generation of autoantibodies or immune complexes. Autoreactive T cells lead to the cellular DTH responses from T_DTh cells or cytotoxic responses from T_C cells.

Diseases caused by parasites are among the leading causes of death and disease in tropical and subtropical regions of the world. 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. Thus, control of these diseases relies heavily on the availability of drugs. 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. This is best dramatized by the global spread of drug resistant Plasmodium falciparum, the organism responsible for the most lethal form of malaria.

Angiogenesis is the fundamental process by which new blood vessels are formed and is essential to a variety of normal body activities (such as reproduction, development and wound repair). Although the process is not completely understood, it is believed to involve a complex interplay of molecules which both stimulate and inhibit the growth of endothelial cells, the primary cells of the capillary blood vessels. Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e., one of no capillary growth) for prolonged periods which may last for as long as weeks or in some cases, decades. When necessary, however, (such as during wound repair), these same cells can undergo rapid proliferation and turnover within a 5 day period (Folkman, J. and Shing, Y., Journal of Biological Chemistry, 267(16): 10931-10934, and Folkman, J. and Klagsbrun, M. (1987) Science, 235: 442-447).

Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as “angiogenic diseases”) are driven by persistent unregulated angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exacerbate an existing pathological condition. For example, ocular neovascularization has been implicated as the most common cause of blindness and dominates approximately 20 eye diseases. In certain existing conditions such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness. Growth and metastasis of solid tumors are also angiogenesis-dependent (Folkman, J. (1986) Cancer Research 46: 467-473 and Folkman, J. (1989) Journal of the National Cancer Institute 82: 4-6). It has been shown, for example, that tumors which enlarge to greater than 2 mm, must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites, such as the liver, lung or bone (Weidner, N., et al. (1991) The New England Journal of Medicine 324(1): 1-8).

Fumagillin is a known compound which has been used as an antimicrobial and antiprotozoal. Its physicochemical properties and method of production are well known (U.S. Pat. No. 2,803,586 and Proc. Nat. Acad. Sci. USA (1962) 48:733-735). Fumagillin and certain types of Fumagillin analogs have also been reported to exhibit anti-angiogenic activity. 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.

Accordingly, there is still a need for angiogenesis inhibitors which are more potent, less neurotoxic, more stable, and/or have longer serum half-lives.

The present invention provides angiogenesis inhibitor compounds which comprise a core, e.g., a Fumagillin core, that is believed to inhibit methionine aminopeptidase 2 (MetAP-2), coupled to a peptide. The present invention is based, at least in part, on the discovery that coupling the MetAP-2 inhibitory core to an amino acid residue or an amino acid derivative prevents the metabolic degradation of the angiogenesis inhibitor compound to ensure a superior pharmacokinetic profile and limits CNS side effects by altering the ability of the angiogenesis inhibitor compound to cross the blood brain barrier. The present invention is also based, at least in part, on the discovery that coupling the MetAP-2 inhibitory core to a peptide comprising a site-directed sequence allows for a cell specific delivery of the angiogenesis inhibitor compound and limits the toxicity of the angiogenesis inhibitor compound.

In one aspect the present invention provides a method for treating a subject (e.g., a mammal, such as a human) suffering from a lymphoid malignancy. The method includes administering to a subject an effective amount of a MetAP-2 inhibitor, thereby treating a subject suffering from a lymphoid malignancy. Lymphoid malignancies which can be treated with a MetAP-2 inhibitor include lymphoid leukemias, such as chronic lymphoid leukemia and acute lymphoid leukemia, and lymphomas, such as T cell lymphoma and B cell lymphoma.

In a preferred embodiment, the method further includes administering to the subject a second therapy suitable for treating a subject suffering from lymphoid malignancy. The second therapy may be administered to the subject subsequent to, simultaneously or prior to administration of the MetAP-2 inhibitor to the subject. The second therapy may include administration of a chemotherapeutic regimen or a vaccine to the subject.

Accordingly, the present invention provides compounds of Formula I,