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Therapeutic applications of pro-apoptotic benzodiazepines

a technology of pro-apoptotic benzodiazepines and therapeutic applications, applied in the field of medicinal chemistry, can solve the problems of difficult treatment of ovarian cancer, pathologic accumulation of t and b cells,

Inactive Publication Date: 2007-02-15
RGT UNIV OF MICHIGAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes methods for treating conditions associated with dysregulation of cell death, such as autoimmune diseases, inflammatory conditions, hyperproliferative disorders, and viral infections, by administering benzodiazepine compounds. These compounds have the ability to induce cell death under low serum conditions. The patent also provides assay methods to identify agents that can induce cell death and prepares medications for treating these conditions. The invention also includes novel benzodiazepine compounds.

Problems solved by technology

The inappropriate survival of these cells results in a pathologic accumulation of T and B cells evidenced by the neoplastic-like growth of lymphoid tissues and high-level autoantibody production.
Ovarian cancer is difficult to treat due to chemoresistance shown by the patient to standard chemotherapy drugs.
Treatment failures are usually attributed to the emergence of chemotherapy resistant cells.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Ability to Induce Cell Death

[0185] Several individual representative compounds that induce apoptosis have been shown above. Of these, the most potent compound is identified as Compound 1, which is shown below.

[0186] Compound 1 was used to induce cell death in a variety of cells by using the above-described materials and methods. Table 1 shows cell viability data after 18 hours of culture with Compound 1 in reduced serum media as described above.

TABLE 14 μMCell LineSourceTypeBz6 μM Bz10 μM BzJurkathumanT-cell000IMRhumanneuroblastoma10000SHSY-5YhumanneuroblastomaNd00ShephumanneuroblastomaNd800293ThumanEmbryonicNdNd30fibroblastRAW 246.7murinemonocytic70%00NIH 3T3murinefibroblastNdNd25

(lower numbers equal increased killing).

Nd = Not determined

example 2

[0187] MRL / MpJ-lpr / lpr (MRL-lpr) mice develop similar serological and histological manifestations of autoimmune disease as human SLE. These mice were developed by a series of cross-breeding of inbred strains until an autoimmune phenotype appeared. (Theofilopoulos A. N. and Dixon F. J. (1985) Adv. Immunol. 37:269-390). The MRL-lpr mice are characterized by the spontaneous development of systemic autoimmune disease. This disease is manifested in several physiological locations and resembles a variety of human diseases. For instance, the kidney damage in these mice is associated with high serological titers of anti-DNA as in human SLE. They also develop an erosive arthropathy and a lymphocytic infiltration of the salivary glands, similar to the human diseases rheumatoid arthritis (RA) and Sjörgen's disease, respectively (Theofilopoulos, supra).

[0188] In general MRL-lpr mice have a profound defect in apoptosis due the mutation of the lpr gene locus. (Sakata K. et al. (1998) Clin. Immun...

example 3

Compound 1 as a Lymphotoxic Agent

Methods

[0210] Animals and Experimental Design:

[0211] Female NZB / W mice (Jackson Labs) were housed in specific pathogen-free, environmentally controlled rooms operated by the University of Michigan's Unit for Laboratory Animal Medicine with 12 hr light-dark cycles and were given food and water ad libitum. Mice were randomly distributed into treatment and control groups. All mice were dosed through intraperitoneal injections using a Hamilton repeating dispenser with glass microliter syringes and 30 gauge needles. Control mice received vehicle (50 μL aqueous DMSO) and treatment mice received Compound 1 dissolved in vehicle. Animal weights were determined weekly, and dosing schedules readjusted thereafter.

[0212] Collection of Blood Tissues:

[0213] Peripheral blood was obtained from the tail veins of all mice for complete blood counts analysis and collection of serum. Blood was first allowed to clot at room temperature for 1 h, and then overnight at ...

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Abstract

Benzodiazepine compounds, and methods for using those compounds are provided. Some of the benzodiazepine compounds include 1,4-benzodiazepine-2-one and 1,4-benzodiazepine-2,5-dione compounds of the following structures: wherein R1, R2, R3 and R4 are as defined. The invention also includes enantiomers, pharmaceutically acceptable salts, prodrugs or derivatives of the benzodiazepine compounds. Any one or more of these benzodiazepine compounds can be used to treat a variety of dysregulatory disorders related to cellular death. Such disorders include autoimmune disorders, inflammatory conditions, hyperproliferative conditions, viral infections, and atherosclerosis. In addition, the above compounds can be used to prepare medicaments to treat the above-described dysregulatory disorders. The benzodiazepines can also be used in drug screening assays and other diagnostic methods.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present disclosure claims priority to U.S. Provisional Application Nos. 60 / 191,855, filed Mar. 24, 2000; 60 / 131,761, filed Apr. 30, 1999; and 60 / 165,511, filed Nov. 15, 1999, the contents of which are hereby incorporated by reference.FIELD OF THE INVENTION [0002] The present invention is in the field of medicinal chemistry and relates to other areas such as pharmacology, biochemistry and organic chemistry. In particular, it provides novel chemical compounds, and their therapeutic uses. BACKGROUND [0003] Multicellular organisms exert precise control over cell number. The normal structure and function of tissues depends on the maintenance of appropriate cell numbers. A balance between cell proliferation and cell death (White, E. (1996) Genes Dev. 10:1-15) achieves this homeostasis. [0004] Cell death occurs in nearly every type of vertebrate cell via necrosis or through a suicidal form of cell death, known as apoptosis. Apoptosis is tr...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5513A61K9/20A61K31/551A61K45/00A61P1/00A61P9/10A61P11/06A61P15/00A61P17/06A61P19/02A61P19/04A61P21/04A61P29/00A61P31/12A61P31/18A61P31/22A61P35/00A61P37/00A61P37/02A61P37/06C07D243/14C07D243/24C07D401/12C07D403/12C07D413/12
CPCA61K31/551A61K31/5513C07D243/14A61K31/55C07D401/12C07D403/12C07D413/12C07D243/24A61P1/00A61P11/06A61P15/00A61P17/06A61P19/02A61P19/04A61P21/04A61P29/00A61P31/12A61P31/18A61P31/22A61P35/00A61P37/00A61P37/02A61P37/06A61P9/10
Inventor GLICK, GARY D.OPIPARI, ANTHONY W. JR.
Owner RGT UNIV OF MICHIGAN
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