Treatment of pulmonary and other conditions
Inventors
Assignees
University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-9862690-B2
Publication Date
2018-01-09
Expiration Date
2034-05-09
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Abstract
Disclosed is a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of: X1-L-X2 wherein L is a linking moiety comprising an enone; andX1 and X2 are each independently an optionally-substituted N-heterocycle. Also disclosed are method for treating pulmonary conditions and other organ or system conditions with the compounds.
Core Innovation
The invention disclosed relates to compounds, or pharmaceutically acceptable salts or esters thereof, having a structure characterized by X1-L-X2, where L is a linking moiety comprising an enone, and X1 and X2 are each independently an optionally-substituted N-heterocycle. Particularly, the compounds include adducts of hydrophilic thiols and enones with at least two N-heterocycles. These compounds are notable for their anti-inflammatory, antioxidant, and other therapeutic properties, and are rendered water-soluble by thiol derivatization, facilitating cellular entry. The compounds are disclosed in various forms, including pharmaceutical compositions suitable for pulmonary delivery, such as nebulized aerosols or dry powders.
The problem being solved addresses the limited efficacy and adverse effects of current treatments for pulmonary diseases, such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, acute lung injury, pulmonary hypertension, and lung cancer. Existing therapies often have limited success in halting disease progression and may involve administration of corticosteroids associated with significant side effects. Furthermore, challenges in delivering effective compounds to the lung, especially by inhalation, necessitate water-soluble and stable formulations. The invention aims to provide novel therapeutic agents with improved solubility and efficacy for pulmonary and other organ or system conditions, overcoming issues such as steroid resistance, inflammation, oxidative damage, fibrotic processes, and tumor proliferation.
Claims Coverage
The patent includes several independent claims focusing on novel compounds and pharmaceutical compositions, with main inventive features related to specific molecular structures and formulations for therapeutic use.
Compounds comprising linked N-heterocycles and an enone linking moiety
A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of X1-L-X2, wherein L is a linking moiety comprising an enone, and X1 and X2 are independently optionally-substituted N-heterocycles, including specific structures where X1 and X2 may be pyrazinyl or pyrimidinyl, and various substitutions including thiol adducts.
Pharmaceutically acceptable salts or esters of the compounds
Compounds in the form of pharmaceutically acceptable salts or esters derived from the base compounds, ensuring suitability for pharmaceutical administration.
Pharmaceutical compositions comprising the compounds
Pharmaceutical compositions containing the disclosed compounds along with at least one pharmaceutically acceptable excipient, formulated as aerosols or dry powders suitable for inhalation.
Specific thiol moieties attached to the compounds
The compounds where the —S—R5 moiety is a thiol derived from N-acetylcysteine, 2-mercaptoethane sulfonate, or glutathione, providing water solubility and biological activity.
The claims cover novel enone-linked N-heterocyclic compounds, their pharmaceutically acceptable derivatives, pharmaceutical compositions including aerosols and dry powders for pulmonary delivery, and specific thiol-derived modifications enhancing solubility and therapeutic functionality.
Stated Advantages
The compounds provide antioxidant and anti-inflammatory effects effective in treating pulmonary diseases and other conditions.
Water solubility of the compounds enables formulation into nebulized aerosols or dry powders for efficient pulmonary delivery.
The compounds show inhibition of pro-inflammatory transcription factors (e.g., NF-κB) and upregulation of antioxidant transcription factors (e.g., Nrf2).
The compounds reduce inflammation, oxidative damage, fibrosis, lung injury, and tumor proliferation.
Nebulized delivery is non-toxic to lung and other tissues even at high doses and prolonged administration.
Therapeutic efficacy demonstrated in multiple disease models including pulmonary fibrosis, acute lung injury, COPD, asthma, pulmonary hypertension, and lung cancer.
Documented Applications
Treatment of various pulmonary diseases including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, acute lung injury (ALI), acute respiratory distress syndrome, pulmonary hypertension, and lung cancer.
Treatment of ischemia-reperfusion injury conditions.
Inhibition of NF-κB activity in subjects.
Inhibition of lung fibroblast proliferation and myofibroblast differentiation.
Amelioration or prevention of acute or chronic rejection of transplanted organs.
Increasing endogenous antioxidant activity via upregulation of Nrf2 transcription factor activity.
Inhibition of pulmonary collagen deposition.
Decreasing proliferation and inducing apoptosis in lung cancer cells.
Improving phagocytic ability of alveolar macrophages.
Diminishing inflammatory responses to allergens and inflammatory, irritating, or cytotoxic agents.
Diminishing allergen-induced airway hyperresponsiveness and airway remodeling.
Diminishing hypoxia-induced remodeling of the pulmonary vasculature.
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