Treatment of pulmonary and other conditions
Inventors
Assignees
University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-10167265-B2
Publication Date
2019-01-01
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 of X1-L-X2, wherein L is a linking moiety comprising an enone and X1 and X2 are each independently an optionally-substituted N-heterocycle. Additionally, the invention includes adducts of hydrophilic thiols and enones comprising at least two N-heterocycles, which render such compounds water-soluble and suitable for therapeutic applications.
The disclosed compounds possess anti-inflammatory, antioxidant, and other therapeutic properties aimed for pulmonary delivery, including via nebulized aerosols or dry powder formulations for inhalation. Methods for treating pulmonary diseases and conditions such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, acute lung injury (ALI), pulmonary hypertension, and lung cancer are disclosed, involving administration of these compounds or pharmaceutical compositions thereof in therapeutically effective amounts.
The problem being addressed arises from the lung's vulnerability to a wide variety of diseases for which effective treatments are limited. Current therapies, particularly corticosteroids, have limited efficacy for several lung diseases and are often accompanied by significant adverse effects. Diseases such as pulmonary fibrosis, COPD, asthma (especially steroid-resistant forms), cystic fibrosis, ALI/ARDS, ischemia-reperfusion injury, pulmonary hypertension, and lung cancer have unmet medical needs due to limited or ineffective therapies, and the disclosed compounds aim to provide improved treatment options.
Claims Coverage
The patent discloses two main independent inventive features focused on methods of treatment using the disclosed compounds with specific structural characteristics.
Methods of treating pulmonary diseases with specified compounds
The method involves administering to a subject a therapeutically effective amount of a compound, or its pharmaceutically acceptable salt or ester, having a structure comprising two optionally-substituted N-heterocycles (X1 and X2) linked via a moiety comprising an enone. X1 and X2 can be optionally-substituted pyrazinyl or pyrimidinyl, and the compound may include variations where X1 and X2 are the same or different. The compound may include moieties such as N-acetylcysteine, 2-mercaptoethane sulfonate, or glutathione. Administration is preferably via inhalation or direct pulmonary delivery.
Methods of modulating biological activities using specified compounds
A method of inhibiting NF-κB activity, lung fibroblast proliferation, myofibroblast differentiation, oxidizing agents in lung tissue; ameliorating or preventing organ rejection; increasing antioxidant activity via upregulating Nrf2 transcription factor; inhibiting pulmonary collagen deposition; diminishing inflammatory responses to allergens, irritants, or bronchoconstrictors; and reducing hypoxia-induced pulmonary vascular remodeling. This is accomplished by administering a therapeutically effective amount of a compound or its pharmaceutically acceptable salt or ester having the specified structure with N-heterocycles and an enone linker.
Methods for decreasing proliferation and inducing apoptosis in lung cancer cells
This method includes contacting lung cancer cells with an effective amount of the disclosed compound or its pharmaceutically acceptable salt or ester having the described structure to decrease proliferation and induce apoptosis.
Methods to improve phagocytotic ability of alveolar macrophages
Improvement in phagocytotic function is achieved by contacting alveolar macrophages with an effective amount of the disclosed compound or its pharmaceutically acceptable salt or ester.
The independent claims primarily cover methods of using compounds characterized by two optionally-substituted N-heterocycles linked by an enone-containing moiety for pulmonary diseases and various biological modulations, including anti-inflammatory, anti-fibrotic, antioxidant, antitumor, and immunomodulatory effects, administered preferably via inhalation or direct pulmonary routes.
Stated Advantages
The compounds possess anti-inflammatory and antioxidant properties.
They can be delivered directly to the pulmonary system efficiently via nebulization.
The compounds show efficacy in inhibiting NF-κB activity and upregulating the antioxidant transcription factor Nrf2.
They inhibit lung fibroblast proliferation and myofibroblast differentiation, which are important in fibrotic processes.
The compounds are non-toxic to lung, liver, and kidney tissues upon long-term high-dose pulmonary delivery.
They reduce pulmonary fibrosis, inflammation, oxidative damage, lung injury, airway hyperresponsiveness, and airway remodeling in various in vivo models.
The compounds decrease proliferation and induce apoptosis in lung cancer cells, demonstrating anti-cancer activity.
They improve phagocytotic ability of alveolar macrophages.
They inhibit pulmonary hypertension and vascular remodeling induced by chronic hypoxia.
Documented Applications
Treatment of pulmonary diseases including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, acute lung injury (ALI), acute respiratory distress syndrome, pulmonary hypertension, lung cancer, and pulmonary manifestations of cystic fibrosis.
Treatment of ischemia-reperfusion conditions in transplanted organs and other tissues.
Inhibition of NF-κB activity and modulation of antioxidant activity in lung tissues and cells.
Inhibition of lung fibroblast proliferation and myofibroblast differentiation to prevent fibrosis.
Amelioration or prevention of acute or chronic rejection of transplanted organs, particularly lungs.
Inhibition of pulmonary collagen deposition and airway remodeling.
Reduction of inflammatory responses to allergens, inflammatory, irritating, or cytotoxic agents.
Diminution of allergen-induced excessive response to bronchoconstrictors such as methacholine.
Decreasing proliferation and inducing apoptosis in lung cancer cells.
Improving phagocytotic ability of alveolar macrophages.
Prevention and treatment of chronic hypoxia-induced pulmonary hypertension and vascular remodeling.
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