Amphiphilic pyridinium compounds, method of making and use thereof
Inventors
Pollard, Harvey B. • Jacobson, Kenneth
Assignees
National Institutes of Health NIH • Henry M Jackson Foundation for Advancedment of Military Medicine Inc
Publication Number
US-7893094-B2
Publication Date
2011-02-22
Expiration Date
2024-06-28
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Abstract
The present invention is directed to the amphiphilic pyridinium compounds, such as for suppressing IL-8 secretion and production. The present invention further provides methods of making and using such compounds for the treatment of the IL-8 related diseases, such as cystic fibrosis.
Core Innovation
The invention describes amphiphilic pyridinium compounds as inhibitors of interleukin-8 (IL-8) secretion and production. These compounds have a specific chemical structure defined by formulas I and II, where R1, R2, and n represent distinct substituents and alkyl chain lengths. The compounds are characterized by the presence of a hydrophobic ester moiety linked to a hydrophilic pyridinium moiety, enabling them to suppress IL-8 secretion in mammalian cells. Methods for synthesizing these compounds and their application for treating diseases related to elevated IL-8 levels, such as cystic fibrosis (CF), are also provided.
The background highlights IL-8 as a cytokine critical in activating immune responses and inflammation, produced by various cell types in response to inflammatory stimuli. Elevated IL-8 levels are associated with numerous diseases, notably CF, where it contributes to lung inflammation and damage by attracting immune cells to the airways. CF is a lethal autosomal recessive disease marked by lung complications resulting from persistent inflammation driven in part by IL-8 hypersecretion. Existing challenges include controlling the elevated IL-8 that exacerbates respiratory difficulties, infections, and overall morbidity and mortality in CF patients.
The invention addresses the problem of aberrant IL-8 secretion linked to inflammatory diseases like CF by providing amphiphilic pyridinium compounds that specifically suppress IL-8 production. Through biochemical synthesis and pharmacological evaluation, certain compounds of defined stereochemistry and alkyl chain length are identified as potent inhibitors of IL-8 secretion with significant specificity and potency. The invention incorporates methods of treatment using these compounds to mitigate IL-8 excess and its deleterious effects in CF and other IL-8 related diseases.
Claims Coverage
There are two independent claims that cover the chemical structure of amphiphilic pyridinium compounds and related pharmaceutical compositions.
Structure of amphiphilic pyridinium compounds
An amphiphilic pyridinium compound with a defined chemical structure involving a pyridinium moiety linked via an alkyl chain to an ester substituent where R1 and R2 groups are specifically selected as detailed in the formulas provided.
Pharmaceutical composition comprising amphiphilic pyridinium compounds
A pharmaceutical composition that includes an amphiphilic pyridinium compound of the defined structure and a pharmaceutically acceptable carrier suitable for various administration routes.
The claims predominantly focus on the specific chemical structure of the amphiphilic pyridinium compounds as IL-8 secretion inhibitors and pharmaceutical compositions containing these compounds, covering both the compounds themselves and their formulation for therapeutic use.
Stated Advantages
The amphiphilic pyridinium compounds effectively suppress IL-8 secretion, which is implicated in inflammatory diseases.
Certain compounds exhibit high potency with submicromolar IC50 values and stereoselectivity, indicating specific interaction with biological targets.
Compounds have a well-defined structure-activity relationship allowing for rational optimization.
The invention provides synthesized compounds capable of alleviating IL-8 mediated pathology in diseases such as cystic fibrosis and other IL-8 associated conditions.
Pharmacogenomics approaches are integrated allowing for tailored therapeutic regimens based on patient genetic profiles.
Documented Applications
Treatment of cystic fibrosis by reducing elevated IL-8 levels to ameliorate lung inflammation.
Therapeutic use in cardiopulmonary bypass operations to reduce IL-8 associated inflammatory responses.
Treatment of cardiopulmonary arrest by mitigating IL-8 mediated morbidity and mortality.
Management of inflammatory bowel diseases via suppression of IL-8 secretion.
Treatment of atherosclerosis through modulation of IL-8 dependent inflammatory pathways.
Use in lung disorders including asthma, bronchial hyperresponsiveness, chronic obstructive pulmonary disease, and nosocomial pneumonia.
Therapeutics for thermal injuries and delayed wound healing by inhibiting IL-8 related inflammation.
Treatment of acute pancreatitis and associated multi-organ dysfunction syndrome.
Therapy for lung injuries including smoke inhalation, acid injury, and reexpansion pulmonary edema through IL-8 suppression.
Management of traumatic brain injury and stroke by reducing brain IL-8 levels to decrease tissue damage.
Treatment of diabetes and its complications, including proliferative diabetic retinopathy, by modulating IL-8 levels.
Reduction of transplant graft rejection incidence by lowering IL-8 mediated inflammatory responses.
Therapeutic applications in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease through IL-8 inhibition.
Treatment of viral infections including HIV/AIDS by interfering with IL-8 secretion and viral replication.
Use as anticancer agents by inhibiting IL-8 mediated tumor growth, development and metastasis.
Treatment of cyclooxygenase inhibitor-resistant fevers by targeting IL-8 signaling pathways.
Use in skin disease such as psoriasis by reducing IL-8 secretion from dermal cells.
Therapeutics for rheumatoid arthritis and related inflammatory disorders by suppressing IL-8 in synovial tissue.
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