Remodilins for airway remodeling and organ fibrosis
Inventors
Solway, Julian • DULIN, Nickolai • LUCI, Diane • Maloney, David • Park, Chan Young • Fredberg, Jeffrey • McCormick, David • Krishnan, Ramaswamy
Assignees
University of Chicago • IIT Research Institute • Beth Israel Deaconess Medical Center Inc • Harvard University • US Department of Health and Human Services
Publication Number
US-12281060-B2
Publication Date
2025-04-22
Expiration Date
2040-04-02
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Abstract
Disclosed herein is a class of molecules termed remodilins that are effective in treating asthma, pulmonary fibrosis, and associated disorders. The molecules ameliorate asthma and pulmonary fibrosis symptoms by various mechanisms, including inhibiting airway smooth muscle contractile protein accumulation, reducing airway constrictor hyperresponsiveness, inhibiting bronchial fibroblast transformation into myofibroblasts, and/or treating or preventing airway or pulmonary fibrosis.
Core Innovation
The invention discloses a class of molecules termed remodilins that are effective in treating asthma, pulmonary fibrosis, and associated disorders. These molecules ameliorate symptoms by inhibiting airway smooth muscle contractile protein accumulation, reducing airway constrictor hyperresponsiveness, inhibiting bronchial fibroblast transformation into myofibroblasts, and treating or preventing airway or pulmonary fibrosis.
Asthma involves airway narrowing, airflow restriction, airway constrictor hyperresponsiveness, airway remodeling, and inflammation. Existing therapies do not inhibit the ability of airway smooth muscle to contract by depleting contractile apparatus proteins. Fibrosis, excessive collagen deposition, and extracellular matrix accumulation further contribute to airway remodeling and fixed airflow obstruction. Myofibroblast transformation (MFT) is a critical pathogenic step in lung fibrosis, and current medications do not directly target MFT.
The remodilins identified herein inhibit accumulation of contractile apparatus proteins such as smooth muscle myosin heavy chain and smooth muscle alpha actin in human airway smooth muscle cells and inhibit transformation of human lung or bronchial fibroblasts into pro-fibrotic myofibroblasts. The compositions comprise compounds of Formula I or Formula II, with defined chemical structures and substituents. Methods include treating diseases of the airway, preventing or inhibiting fibrosis (pulmonary and other organ fibrosis), fibroblast transformation into myofibroblasts, smooth muscle contractile protein accumulation, airway constrictor hyperresponsiveness, and asthma, by administering these compounds.
Claims Coverage
There are three identified independent claims focusing on compositions and methods involving compounds of Formula I and II and their therapeutic application.
Composition comprising compounds of Formula I
A pharmaceutical composition comprising a compound of Formula I, with specific chemical definitions and substituents, or a salt, enantiomer, or diastereomer thereof.
Composition comprising compounds of Formula II
A pharmaceutical composition comprising a compound of Formula II, with specific chemical definitions and substituents, or a salt, enantiomer, or diastereomer thereof.
Methods of treatment using compounds of Formula I or II
Methods for treating diseases of the airway and fibrosis, preventing or inhibiting fibroblast transformation into myofibroblasts and smooth muscle contractile protein accumulation, and treating asthma or airway constrictor hyperresponsiveness, by administering compounds of Formula I or II. These methods include diseases such as idiopathic pulmonary fibrosis, allergic asthma, exercise-induced asthma, and other types enumerated explicitly.
The independent claims encompass compositions comprising compounds of Formula I and II, and methods of treating airway diseases and fibrosis using these compounds, highlighting their chemical structures and application in diseases related to airway remodeling, fibrosis, and asthma.
Stated Advantages
Remodilins act at underlying disorders associated with asthma and pulmonary fibrosis, providing improved therapeutic effects over existing treatments.
Remodilins specifically inhibit airway smooth muscle contractile protein accumulation, myofibroblast transformation, and airway constrictor hyperresponsiveness, which prior therapies do not target.
Selective lung accumulation after oral administration allows for effective dose delivery and potential reduced systemic side effects.
Potential to prevent or reverse lung scarring in idiopathic pulmonary fibrosis by blocking myofibroblast transformation, a checkpoint step not targeted by current drugs.
Documented Applications
Treatment of asthma, including various types such as allergic asthma, exercise-induced asthma, cough variant asthma, occupational asthma, nocturnal asthma, adult- or childhood-onset asthma, obesity-associated asthma, and asthma associated with other airways diseases.
Treatment or prevention of pulmonary fibrosis, including idiopathic pulmonary fibrosis, fibrosis accompanying diseases such as sarcoidosis, collagen vascular diseases, drug toxicity-induced fibrosis, and radiation-induced fibrosis.
Treatment of organ fibrosis outside the lung, including in the liver, heart, kidney, skin, and bone marrow.
Inhibition of airway smooth muscle contractile protein accumulation and airway constrictor hyperresponsiveness.
Inhibition of fibroblast transformation into myofibroblasts, implicated in fibrosis development.
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