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Small molecule inhibitors of necroptosis

a small molecule inhibitor and necroptosis technology, applied in the field of compound and cell death, can solve the problems of complex underlying cell death mechanisms resulting in these two phenotypes and the control of necrosis is not as well understood, and achieve the effect of reducing necroptosis

Inactive Publication Date: 2012-05-17
PRESIDENT & FELLOWS OF HARVARD COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0196]By “effective amount” or “therapeutically effective amount” of an agent, as used herein, is that amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, an effective amount depends upon the context in which it is being applie

Problems solved by technology

While much is known about the mechanisms of action that control apoptosis, control of necrosis is not as well understood.
More recent studies, however, demonstrate that the underlying cell death mechanisms resulting in these two phenotypes are much more complicated and, under some circumstances, interrelated.

Method used

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  • Small molecule inhibitors of necroptosis
  • Small molecule inhibitors of necroptosis
  • Small molecule inhibitors of necroptosis

Examples

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example 1

Determination of Necroptosis Inhibitory Activity

[0443]Evaluation of necroptosis inhibitory activity was performed using a FADD-deficient variant of human Jurkat T cells or with L929 cells treated with TNF-α as previously described (Degterev et al., Nat. Chem. Biol. 1:112 (2005) and Jagtap et al., J. Med. Chem. 50: 1886 (2007)). Utilizing these conditions the cells efficiently underwent necroptosis. For EC50 value determinations, cells were treated with 10 ng / mL of human TNF-α in the presence of increasing concentration of test compounds for 24 hours followed by ATP-based viability assessment.

[0444]ATP-based viability assessment: Briefly, necroptosis activity was performed using a FADD-deficient variant of human Jurkat T cells or L929 cells treated with TNF-α. For EC50 value determinations, cells (500,000 cells / mL, 100 μL per well in a 96-well plate) were treated with 10 ng / mL of human TNF-α in the presence of increasing concentration of test compounds for 24 hours at 37° C. in a hum...

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Abstract

The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-α) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I)-(VIII) and by Compounds (I)-(I), (13)-(26), (27)-(33), (48)-(57), and (58)-(70). These necrostatins are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring necrostatins. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims benefit of U.S. Provisional Application No. 61 / 140,615, filed Dec. 23, 2008, which is hereby incorporated by reference.STATEMENT AS TO FEDERALLY SPONSORED RESEARCH[0002]This invention was made with government support under UO1 NS050560 awarded by the National Institutes of Health. The U.S. government has certain rights to this invention.FIELD OF THE INVENTION[0003]The invention relates to compounds and to cell death, in particular through necrosis and necroptosis, and regulation thereof by small molecules.BACKGROUND OF THE INVENTION[0004]In many diseases, cell death is mediated through apoptotic and / or necrotic pathways. While much is known about the mechanisms of action that control apoptosis, control of necrosis is not as well understood. Understanding the mechanisms regulating both necrosis and apoptosis in cells is essential to being able to treat conditions, such as neurodegenerative diseases, stroke, coronary...

Claims

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Application Information

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IPC IPC(8): A61K31/519C07D257/04C07D403/06C07D417/12C07D403/12C07C35/37C07C33/38C07C35/44C07D495/14C07D495/04A61P25/00A61P13/12A61P9/00A61P3/10A61P31/12A61P29/00A61P11/06A61P1/18A61P1/16A61P27/02A61P21/00C07D231/06
CPCC07D209/08C07D277/18C07D215/08C07D231/06C07D231/12C07D231/56C07D277/46C07D307/52C07D333/20C07D403/06C07D403/12C07D405/06C07D417/12C07D495/04C07D498/08C07C35/37C07C33/38C07D211/78C07D211/90C07D233/02A61P1/00A61P1/04A61P1/14A61P1/16A61P1/18A61P11/00A61P11/06A61P13/12A61P19/08A61P21/00A61P21/04A61P25/00A61P25/02A61P25/28A61P27/00A61P27/02A61P29/00A61P31/04A61P31/06A61P31/12A61P35/00A61P37/00A61P37/02A61P37/06A61P7/00A61P9/00A61P9/10A61P3/10
Inventor YUAN, JUNYINGHSU, EMILY S.
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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