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Purine and pyrimidine cdk inhibitors and their use for the treatment of autoimmune diseases

An autoimmune and inhibitory technology, which is applied in the field of CDK2 and/or CDK7 and/or CDK9 inhibitors to treat diseases related to antinuclear antibodies, and can solve side effects and other problems

Inactive Publication Date: 2007-10-03
CYCLACEL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many of the treatments currently available are associated with serious side effects

Method used

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  • Purine and pyrimidine cdk inhibitors and their use for the treatment of autoimmune diseases
  • Purine and pyrimidine cdk inhibitors and their use for the treatment of autoimmune diseases
  • Purine and pyrimidine cdk inhibitors and their use for the treatment of autoimmune diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0190] NZBxNZW F1 mice were randomly divided into the following groups:

[0191] Group 1 (n=18): mice gavaged with vehicle (HCl 50 mM) daily;

[0192] Group 2 (n=17): mice fed with CYC202 (200 mg / kg) daily;

[0193] Group 3 (n=19): Mice fed with CYC202 (100 mg / kg) daily;

[0194] Treatment started at 2 months of age (prevention study) and continued until 8 months of age; at 5 months of age, 4-5 animals per group were sacrificed to assess levels of serum BUN and circulating anti-DNA antibodies.

[0195] Another group, group 4 (n=14 mice), was gavaged daily with CYC202 (100 mg / kg) starting at 5 months of age and continued until 8 months of age, at which point immune complex precipitation had actually occurred ( treatment research). Five normal CD-1 mice (Charles River Italia, Calco, Italy) served as controls.

[0196] The following parameters are evaluated:

[0197] Urinary protein excretion: measured monthly until 5 months of age, then every 2 weeks.

[0198] At execution...

Embodiment 2

[0205] Lupus mice were randomly divided into the following groups:

[0206] Group 1 (n=10): mice gavaged with vehicle (HCl 50 mM) daily;

[0207] Group 2 (n=15): Mice fed with CYC202 daily at a dose of 200 mg / kg;

[0208] Group 3 (n=12): Mice were injected intraperitoneally with methylprednisolone (MPS, Urbason, Hoechst s.p.a, Milano, Italy) daily at a dose of 1.5 mg / kg;

[0209] Group 4 (n=16): mice dosed daily with CYC202 (200 mg / kg) in combination with MPS (1.5 mg / kg).

[0210] Treatment started at 5 months of age, when immune complex precipitation had actually occurred, and continued until 12 months of age, when the last animal to receive vehicle treatment died. Five normal CD-1 mice (Charles River Italia, Calco, Italy) served as controls.

[0211] The following parameters are evaluated:

[0212] Survival rate;

[0213] Urinary protein excretion: measured monthly until 5 months of age, then every 2 weeks.

[0214] Serum BUN: measured at 5 months of age (before treatm...

Embodiment 1 and 2

[0217] Examples 1 and 2: Materials and methods

[0218] Proteinuria and Renal Function

[0219] Proteinuria concentrations were determined by the Coomassie Brilliant Blue G dye-binding assay with bovine serum albumin as the standard. Renal function was evaluated by BUN in heparinized blood by Reflotron test (Roche Diagnostics corporation, Indianapolis, USA). BUN levels above 30 mg / dl are considered abnormal (the normal range for mice is considered by this laboratory to be 14-29 mg / dl).

[0220] anti-DNA antibody

[0221] Levels of autoantibodies against dsDNA in serum were assessed by an enzyme immunoassay as previously described (Kidney Int, 53:726-734, 1998) (Diastat anti-dsDNA kit, Bouty Laboratory, Milano, Italy).

[0222] serum transaminase

[0223] Serum levels of AST and ALT were measured using an automated analyzer (CX5, Beckman Instruments Inc., Fullerton, CA).

[0224] Renal Morphology

[0225] Light Microscopy: Renal cortex fragments were fixed in Dubosq-Brazi...

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PUM

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Abstract

The present invention relates to the use of an inhibitor of CDK2 and / or CDK7 and / or CDK9, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease associated with antinuclear antibodies, wherein the inhibitor of CDK2 and / or CDK7 and / or CDK9 or pharmaceutically acceptable salt thereof is administered in an amount sufficient to down-regulate the levels of antinuclear antibodies. A further aspect of the invention relates to a combination comprising an inhibitor of CDK2 and / or CDK7 and / or CDK9, or a pharmaceutically acceptable salt thereof, and methylprednisolone, and its use in the treatment of diseases associated with antinuclear antibodies, such as SLE.

Description

[0001] The present invention relates to a method of treating diseases related to antinuclear antibodies. More specifically, but not exclusively, the present invention relates to methods of treatment of autoimmune rheumatic diseases, such as human systemic lupus erythematosus (SLE), as well as pharmaceutical compositions and combinations thereof. Background of the invention [0002] The purpose of the immune system is to protect the body from potentially harmful substances (antigens), such as microorganisms, toxins, cancer cells, and foreign blood or tissue from another person or species. Antigens are destroyed by an immune response that includes the production of antibodies (molecules that bind to the antigen and make it easier to destroy) and the activation of lymphocytes (specific white blood cells that recognize and destroy specific antigens). [0003] Immune system disorders occur when the immune response is inappropriate, excessive or lacking. Autoimmune disease refers t...

Claims

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Application Information

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IPC IPC(8): A61K31/52A61P37/06A61K31/505A61P43/00A61P19/02
Inventor 阿里拉·贝尼格尼卡拉·佐加朱斯普·雷马齐阿索斯·詹内拉-博拉多里
Owner CYCLACEL
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