Polyether brevetoxin derivatives as a treatment for cystic fibrosis, mucociliary dysfunction, and pulmonary diseases
Inventors
Baden, Daniel G. • Abraham, William M. • Bourdelais, Andrea J.
Assignees
University of North Carolina at Wilmington
Publication Number
US-7399782-B2
Publication Date
2008-07-15
Expiration Date
2024-09-20
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Abstract
Disclosed are compounds that are derivatives of brevetoxin, or PbTx, pharmaceutical formulations comprising the compounds, and methods of regulating mucus transport in a cell, treating mucociliary dysfunction and diseases related to decreased mucus transport, wherein the compounds are of the Formula (I), and Formula (III): wherein R, R1, R2, R3, A, n, and Y are as defined herein for each compound.
Core Innovation
The invention provides polyether brevetoxin derivatives, as well as their pharmaceutically acceptable salts, solvates, hydrates, complexes, or combinations, that have specific structural modifications as described by Formulas (I), (II), (III), and (IV). These compounds and their pharmaceutical formulations are designed for the regulation of mucus transport in cells and the treatment of diseases associated with decreased mucus transport or mucociliary dysfunction. The invention also extends to pharmaceutical formulations comprising these compounds and methods of regulating mucus transport velocity in a subject.
The background of the invention highlights the problem that decreased mucus transport is a hallmark of diseases such as airway obstruction, asthma, pulmonary disease, pulmonary infections, and particularly cystic fibrosis. Cystic fibrosis is caused by defects in a gene coding for a sodium/chloride transporter, resulting in defective transport of sodium and chloride by epithelial cells and leading to issues such as bronchoconstriction and impaired mucus transport.
The core solution provided by the invention is the use of brevetoxin derivatives that modulate voltage-gated sodium channels. By regulating these channels, the compounds described can assist in restoring normal mucus transport, thereby treating or preventing diseases and symptoms associated with mucociliary dysfunction or decreased mucus transport. The invention specifies compositions, methods of administration, and specific structural examples of these brevetoxin derivatives, laying out a platform for therapeutic intervention in conditions such as cystic fibrosis, asthma, and related pulmonary diseases.
Claims Coverage
There are two independent method claims, each outlining a distinct inventive feature regarding the use of brevetoxin derivatives in specific disease contexts.
Reducing the severity or delaying the onset of symptoms of cystic fibrosis or asthma by administering brevetoxin derivatives
This inventive feature is directed to a method involving administering to a subject in need a therapeutically effective amount of a compound of Formula X, or a pharmaceutically acceptable salt, for reducing the severity or delaying the onset of symptoms associated with cystic fibrosis or asthma.
Treating cystic fibrosis or asthma by administering brevetoxin derivatives of Formula (III)
This inventive feature consists of a method of treating cystic fibrosis or asthma in a subject by administering a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt.
The inventive features center on the administration of specific brevetoxin derivatives for reducing, delaying, or treating the symptoms of cystic fibrosis or asthma in a subject.
Stated Advantages
The compounds are useful for slowing the progression of disease symptoms associated with decreased mucus transport.
The compounds are useful for preventing the further progression of disease symptoms associated with mucociliary dysfunction.
The invention can delay or slow the progression or prevent further progression of diseases such as cystic fibrosis, asthma, and pulmonary disease, thereby giving the individual a more useful life span.
Documented Applications
Treatment or prevention of diseases associated with decreased mucus transport, including chronic airway obstruction, asthma, pulmonary disease, pulmonary infection, and cystic fibrosis.
Regulation of mucus transport velocity in subjects or cells.
Treatment of industrial-related diseases or conditions caused or exacerbated by inhaling gases, particles of textiles, grit, or other industrial particles or fumes.
Clearing pathogenic particles, such as particles that comprise bacteria, including anthrax, or fungus particles.
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