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Inhibition of Bid-Induced Cell-Death Using Small Organic Molecules

a small organic molecule and cell death technology, applied in the field of compounds, can solve the problems of cell death, no such therapeutic agent has been developed,

Inactive Publication Date: 2010-10-14
THE BURNHAM INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]The present invention provides for fragment-based designing of certain chemical compounds such as BID-inhibitors, and for methods of use thereof for treatment of various diseases, disorders, and pathologies, for example, various kinds of neurodegenerative diseases, liver inflammation, multiple sclerosis, heart disease, ischemic injury and other diseases where BID has been implicated. As shown by the schematic representation of death receptor activation (FIG. 1A), apoptosis usually occurs after being induced by caspase-8 mediated BID activation. However, using compounds capable of blocking BID migration, such as compound II described below, can result in cell survival (FIG. 1B).
[0011]The compounds described in this invention, such as 4-phenylsulfanyl-phenylamine derivatives, may be beneficial for treatment of the diseases where the treatment includes inhibition of BID, modulating caspase activity, and protection against cell death.

Problems solved by technology

The apoptotic cascade in cells is known to lead to cell death.
Unfortunately, no such therapeutic agents have been developed.

Method used

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  • Inhibition of Bid-Induced Cell-Death Using Small Organic Molecules
  • Inhibition of Bid-Induced Cell-Death Using Small Organic Molecules
  • Inhibition of Bid-Induced Cell-Death Using Small Organic Molecules

Examples

Experimental program
Comparison scheme
Effect test

example 1

General Materials and Methods

Library Design

[0084]A library design approach was used. The NMR compound library was composed of about 300 low molecular weight compounds representing diverse core structures. This library was assembled and individual 1D 1H spectra were measured in D2O buffer as control of compound purity, stability, and solubility in water buffer. The compounds having reactive functional groups such as halides, anhydrides, epoxides, aziridines, phosphonates and sulphonates esters, imines, aldehydes, Michael acceptors, halopyrimidines, were not included in the library. The following criteria were adopted for selection of the compounds for the library: average molecular weight was less than 300 Daltons; octanol / water repartition coefficient (LogP) was less than 1.3; number of rotatable bonds was between 0 and 2. The library was designed to optimize the detection of trNOEs and ILOEs by selecting compounds with appropriate derivatization of functional groups with proton NMR...

example 2

Synthesis of N-((4-(4-aminophenylthio)phenylcarbamoyl)methyl)-2,4-dihydroxybenzamide (Compound I)

[0092]

[0093]The synthesis of the title Compound I is shown schematically on FIGS. 5A and 7. Briefly, the formation of the peptide bond was aided by resin-bound carbodiimide, such as N-cyclohexylcarbodiimide-N′-propylmethyl polystyrene (PS-CDT) (available from) Argonaut Technologies) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WS-CDI resin), using as starting materials the commercially available 4-amino-4′-nitrodiphenyl sulfide (available from Aldrich) and 4-[(tert-butoxycarbonyl)amino]butanoic acid (Boc-GABA-OH, available from Novabiochem). Stirring the reaction mixture at room temperature resulted in the corresponding Boc-protected amine (Compound VI, also shown above in the application). De-protection with trifluoroacetic acid (TFA) gave the free amine (Compound VII), with good yield. Following reaction with 4-methoxybenzenesulfonyl chloride afforded the correspondi...

example 3

Synthesis of {3-[4-(4-nitro-phenylsulfanyl)-phenylcarbamoyl]propyl}-carbamic acid tert-butyl ester (Compound VI)

[0095]

[0096]To synthesize the title Compound VI, PS-CDI resin described in Example 2 (730 mg, 1.0 mmol) was added to a dry round bottomed flask. t-Boc-4-aminobutanoic acid (152 mg, 0.75 mmol) was added as a solution in CH2Cl2 (4 ml) and the reaction mixture was stirred at room temperature. After 5 minutes, 4-amino-4′-nitrodiphenyl sulfide (123 mg, 0.5 mmol) in 4 ml of CH2Cl2 was added and the suspension stirred at room temperature for 4 days. The reaction mixture was filtered under vacuum and the resin was washed twice with CH2Cl2. Concentration of the filtrate afforded a crude that was purified by flash chromatography (hexane / ethyl acetate 1:1) to give the pure title Compound VI (274 mg, 64%) as a yellow solid, together with unreacted starting material (25 mg, 20%).

[0097]The following spectral data was obtained for the title Compound VI: 1H NMR (d-DMSO, 500 MHz): 10.19 (s...

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Abstract

Various phenylamine derivatives are described as well as the use of compounds to inhibit BID protein for controlling apoptotic cascade.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional application of U.S. application Ser. No. 11 / 645,239 filed Dec. 22, 2006, now issued as U.S. Pat. No. 7,741,521; which is a continuation-in-part application of International Application No. PCT / US2005 / 022640 filed Jun. 27, 2005; which claims the benefit under 35 USC §119(e) to U.S. Application Ser. No. 60 / 583,189 filed Jun. 25, 2004, now expired. The disclosure of each of the prior applications is considered part of and is incorporated by reference in the disclosure of this application.GRANT INFORMATION[0002]The invention was made with government support under Grant Nos. HG01642, 5T32-GM07616, CA78040, and CA30199-22 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The present invention relates generally to the use of compounds to treat a variety of disorders, diseases and pathologic conditions an...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/27C07C237/52A61K31/167A61P1/16A61P9/10A61P25/28A61P25/16C07C323/41C07C237/04C07C311/29G01N33/53A61K31/18
CPCG01N2500/04C07C323/41A61P1/16A61P25/16A61P25/28A61P9/10
Inventor REED, JOHN C.PELLECCHIA, MAURIZIO
Owner THE BURNHAM INST
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