Method for treatment of cytokine release syndrome
Inventors
Lee, In-Kyu • Jeon, Jae-Han • CHANDA, Dipanjan • Choi, Eun Jung • Jung, Hoe-Yune • LEE, Heon Jong
Assignees
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Publication Number
US-11850246-B2
Publication Date
2023-12-26
Expiration Date
Abstract
A composition for preventing and/or treating cytokine release syndrome and a method of prevention and/or treatment of cytokine release syndrome are disclosed. The composition includes an aryl ethene compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient. The method includes administering the aryl ethene compound, an isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof, in an effective amount to a subject in need thereof. The cytokine release syndrome may be caused by virulent infection. The administration of the compound reduces the pre-inflammatory cytokine levels in the subject.
Core Innovation
The invention relates to treating or managing cytokine release syndrome in a subject in need thereof by administering an effective amount of an aryl/arylethene ERRg inhibitor compound selected from the compounds described in Chemical Formulas 1, 2, and 6. The disclosure includes isomers, pharmaceutically acceptable salts, and solvates of the compounds, including (E)-configured example compounds. The treatment comprises reducing a level of a cytokine in serum of the subject by targeting serum pro-inflammatory cytokine levels.
The problem addressed is cytokine release syndrome caused by an acute inflammatory disorder or virulent infection, including virulent infection- or cytokine-storm-induced disease such as sepsis/septic shock and pneumonia. The disclosed approach is presented as reducing multiple pro-inflammatory cytokines in serum, including IFNβ, IL-1β, TNFα, and IL-6. The disclosure frames CRS in terms of hypercytokinemia and virulent infection-associated inflammatory responses.
The compounds are described as estrogen-related receptor gamma (ERRg) inhibitor aryl/arylethene compounds, and the disclosure provides Markush definitions for substituents of the chemical formulas. Specific (E)-configured example compounds are named, including DMRC200434/18a, DMRC2001000/18k, DMRC200699/22i, and DMRC200996/22r. The document also describes pharmaceutical compositions comprising the compounds and pharmaceutical excipient/carrier, with oral, parenteral, and rectal forms for method-of-use embodiments.
Supporting findings are disclosed via suppression of macrophage inflammatory markers and delayed endotoxin-mediated death in an LPS-induced endotoxemia model. The mechanistic framing ties the serum cytokine reduction outcome to inflammatory responses associated with macrophages. Additional context in the disclosure includes CD40, CD80, and CD86 as macrophage-associated inflammatory markers.
Claims Coverage
Two independent claims are identified: clm-00001 and clm-00008. Across the independent claims, the coverage includes administering an effective amount of a compound, including isomers, pharmaceutically acceptable salts, and solvates, as an ERRg inhibitor to treat CRS, and independently diminishing supraphysiological levels of selected cytokines in virulent infection or acute inflammatory disorder.
Errg inhibitor compound administration to treat or manage CRS by reducing serum cytokine level
A method for treating or managing cytokine release syndrome caused by an acute inflammatory disorder or virulent infection by administering an effective amount of a compound selected from the compounds described in the disclosure, including an isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein treating or managing the cytokine release syndrome comprises reducing a level of a cytokine in serum of the subject.
Errg inhibitor compound to diminish supraphysiological cytokine levels in virulent infection or acute inflammatory disorder
A method for diminishing supraphysiological levels of one or more selected from the group consisting of IFNβ, IL-1β, TNFα, and IL-6 in a subject in need thereof by administering an effective amount of a compound selected from the compounds described in the disclosure, including an isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the subject suffers from a virulent infection or acute inflammatory disorder.
The independent claims broadly cover CRS management through serum cytokine reduction using ERRg inhibitor aryl/arylethene compounds defined by the disclosure’s chemical formulas, including isomers, pharmaceutically acceptable salts, and solvates, with one independent claim focused on CRS caused by acute inflammatory disorder or virulent infection and the other focused on diminishing supraphysiological levels of IFNβ, IL-1β, TNFα, and IL-6 in those conditions.
Stated Advantages
Reduces pro-inflammatory cytokine levels in serum (IFNβ, IL-1β, TNFα, IL-6) in cytokine release syndrome.
Diminishes supraphysiological levels of selected cytokines (IFNβ, IL-1β, TNFα, IL-6).
Suppresses macrophage inflammatory markers.
Delays endotoxin-mediated death in an LPS-induced endotoxemia model.
Reduces LPS-induced upregulation of macrophage activation markers CD40, CD80, and CD86.
Suggests potential treatment of cytokine release syndrome.
Documented Applications
Treating or managing cytokine release syndrome caused by an acute inflammatory disorder or virulent infection.
Treating or managing virulent infection- or cytokine-storm-induced disease including sepsis/septic shock.
Treating or managing pneumonia associated with cytokine release syndrome.
Reducing hypercytokinemia by diminishing supraphysiological levels of IFNβ, IL-1β, TNFα, and IL-6 during virulent infection or acute inflammatory disorder.
LPS-induced endotoxemia model involving suppression of macrophage inflammatory markers and delayed endotoxin-mediated death.
In vitro macrophage study in which DMRC200434 (compound 18a) reduces LPS-induced upregulation of CD40, CD80, and CD86.
In vivo LPS-induced endotoxemia model in C57BL/6 mice in which DMRC200434 delays endotoxin-mediated death.
Potential treatment of cytokine release syndrome, as suggested by the disclosed findings.
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