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Novel CD40:CD154 binding interruptor compounds and use thereof to treat immunological complications

a technology of interruptor compounds and cd154, which is applied in the field of cd40 : cd154 binding interrupter compounds, can solve the problems of impaired memory b cell development, impaired spleen and lymph node germinal centers, and deficient ability of murine nullizygotes to figh

Inactive Publication Date: 2007-10-25
ZHENG ZHONGLI +11
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides new compounds that can stop the interaction between CD154 and CD40. These compounds can be used to develop pharmaceutical compositions and treat conditions associated with inappropriate CD154 activation.

Problems solved by technology

In the absence of a functional CD40:CD154 interaction, spleen and lymph node germinal centers do not develop properly, and the development of memory B cells is impaired.
Murine nullizygotes are deficient in their ability to fight Leishmania infection.

Method used

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  • Novel CD40:CD154 binding interruptor compounds and use thereof to treat immunological complications
  • Novel CD40:CD154 binding interruptor compounds and use thereof to treat immunological complications
  • Novel CD40:CD154 binding interruptor compounds and use thereof to treat immunological complications

Examples

Experimental program
Comparison scheme
Effect test

example 1

Chemical Synthesis of Compound 7

[0112] Step 1: A mixture of chelidamic acid monohydrate (1.00 g, 4.97 mmol) and phosphorus pentabromide (8.45 g, 19.6 mmol) was warmed to 90° C. for 3 hours (h). Chloroform (100 mL) was added to the warm reaction mixture and the resulting slurry was filtered. The filtrate was concentrated in vacuo to give a pink solid. The solid was dissolved in ethanol (vigorous reaction), stirred for 0.5 h and then concentrated in vacuo to give a yellow solid. The solid was dissolved in ether (250 mL), washed with saturated aqueous sodium bicarbonate (50 mL×2), dried (MgSO4) and concentrated in vacuo to give 1.30 g of a white solid.

[0113] Step 2: A solution of KOH (0.83 g, 3.31 mmol) in anhydrous ethanol (40 mL) was added dropwise to a solution of the compound from step 1 (3.85 g, 12.7 mmol) in anhydrous ethanol (100 mL) over the course of 3 h. A white precipitate formed. The unstirred slurry was allowed to sit at room temperature (RT) for 7 h and then at 0° C. ov...

example 2

Chemical Synthesis of Compound 8

[0122] Step 1: steps 1-9 of EXAMPLE 1 were carried out.

[0123] Step 2: Catalytic 10% Pd / C was added to a solution of the compound from step 1 (0.100 g) in ethyl acetate. The reaction was stirred under a hydrogen atmosphere (1 atm) overnight. The reaction was then centrifuged and the supernatant decanted and concentrated in vacuo.

[0124] Step 3: A solution of the compound from step 2 (0.020 g) in 2:1 TFA / methylene chloride (6 mL) was stirred at RT for 2 h. The reaction was then concentrated in vacuo and purified via reverse phase HPLC (acetonitrile / water) to give an off-white solid.

example 3

Chemical Synthesis of Compound 4

[0125] Step 1: steps 1 and 2 of EXAMPLE 1 were carried out.

[0126] Step 2: Catalytic DMF and 2.0 M oxalyl chloride / dichloromethane (3.0 mL, 6.0 mmol) were added to a solution of the compound from step 1 (2.72 g, 2.64 mmol) in dichloromethane (20 mL) at RT. The reaction solution was stirred until bubbling ceased, diluted with toluene (40 mL) and reduced in volume in vacuo. A solution of 3-phenyl-1-propylamine (1.7 mL, 11.9 mmol) in pyridine (8 mL) was added and the resulting solution was stirred at RT overnight. The reaction solution was diluted with ethyl acetate (300 mL), washed with water (150 mL), 1N HCl (150 mL×3) and water (150 mL), dried (MgSO4) and concentrated in vacuo to give an oil. The oil was dissolved in 1:1 saturated aqueous lithium hydroxide / THF and stirred overnight at RT. The reaction was then acidified with 1N HCl, extracted with ethyl acetate, dried (MgSO4) and concentrated in vacuo to give 3.456 g of an oil.

[0127] Step 3: A solut...

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Abstract

The present invention relates to novel CD40:CD154 binding interrupter compounds and use of these compounds and pharmaceutical compositions comprising them, to treat conditions associated with inappropriate CD154 activation in a subject. Specifically, this invention provides compounds which are identified by screening a library of small molecules for those that are capable of specifically binding CD154 and interrupting CD40:CD154 interaction.

Description

TECHNICAL FIELD OF THE INVENTION [0001] The present invention relates to novel CD40:CD154 binding interrupter compounds and use of these compounds and pharmaceutical compositions comprising them, to treat conditions associated with inappropriate CD154 activation in a subject. Specifically, this invention provides compounds which are identified by screening a library of small molecules for those that are capable of specifically binding CD154 and interrupting CD40:CD154 interaction. BACKGROUND OF THE INVENTION [0002] Data establishing that T cell activation requires both T cell receptor (“TCR”) mediated signals and simultaneously delivered costimulatory signals have accumulated over the past twenty years. For example, antibody production by B lymphocytes in response to protein antigens requires a specific, costimulatory interaction with T lymphocytes. This B cell / T cell interaction is mediated through several receptor-ligand binding events in addition to engagement of the TCR. See, e....

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/44A61P37/08C07C303/00C07D213/44F25B9/00A61K31/444A61P1/04A61P1/16A61P9/02A61P9/04A61P9/10A61P11/00A61P11/06A61P13/12A61P17/06A61P19/02A61P25/28A61P27/02A61P29/00A61P35/02A61P37/00A61P37/06C07C311/47C07D401/14F25B9/14
CPCC07C311/47A61K31/444C07D401/14A61P1/04A61P1/16A61P9/02A61P9/04A61P9/10A61P11/00A61P11/06A61P13/12A61P17/06A61P19/02A61P25/28A61P27/02A61P29/00A61P35/02A61P37/00A61P37/06A61P37/08F25B9/10F25B9/145F25B2309/1408F25B2309/1411F25B2309/1418F25B2309/1424F25B2309/14241
Inventor ZHENG, ZHONGLICARTER, MARY BETHLIAO, YUSHENGSUN, LIHONGKIRKOVSKY, LEONIDMROSE, SUSANHSU, YEN-MINGTHOMAS, DAVIDSHIPPS, GERALD W. JR.JINDAL, SATISHLENZ, GEORGE R.NASH, HUW M.
Owner ZHENG ZHONGLI
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