Polyether brevetoxin derivatives as a treatment for cystic fibrosis, mucociliary dysfunction, and pulmonary diseases
View Patent ↗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, R 1 , R 2 , R 3 , A, n, and Y are as defined herein for each compound.
1. A method of reducing the severity of or delaying the onset of symptoms associated with cystic fibrosis or asthma in a subject comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula X, or a pharmaceutically acceptable salt, where Formula X is:
wherein
A is
R is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkyl ester, C 2 -C 6 alkenyl ester, amino, amido, aryl ester, cycloalkyl ester, cycloalkenyl ester, purinyl, pyrimidinyl, heterocyclyl, aryl, or heteroaryl;
R 1 is H or —(CO)CH 3 ; and
R 2 and R 3 at each occurrence are independently —CH 2 (CO)CH 3 , —CH 2 (CO)CH 2 CH 3 , —CH 2 (CO)CH(CH 3 ) 2 , —CH 2 (CO)CH 2 CH 2 CH 3 , —CH 2 (CO)CH(CH 3 )CH 2 CH 3 , or —CH 2 (CO)CH 2 CH(CH 3 ) 2 ,
or OR 2 and OR 3 can be taken together to form a six membered ring of the formula (Ia)
wherein X is CH, C═O, or CH(CH 3 );
wherein the bracketed-dashed bonds indicate attachment to backbone;
Y is CH═CH, C═O, CHCH 3 , or CH 2 ;
n is 1 or 0.
2. A method of treating cystic fibrosis or asthma in a subject comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, where Formula (III) is:
wherein
R is H, OH, halogen, C 1 -C 6 lower alkyl, C 1 -C 6 alkyl ester, C 2 -C 6 alkenyl ester, amino, amido, aldehyde, aryl ester, cycloalkyl ester, cycloalkenyl ester, purinyl, pyrimidinyl, heterocyclyl, aryl, or heteroaryl;
Y is C═O, CH═CH, CHCH 3 or CH 2 ; and
n is 1 or 0.
3. A method according to claims 1 , wherein the therapeutically effective amount is administered in a dosage of between about 0.1 pg to about 100 mg per day.
4. A method according to claim 3 , wherein the therapeutically effective amount is a dosage of between about 0.1 pg to about 10 μg per day.
5. A method according to claim 2 , wherein the therapeutically effective amount is a dosage of between about 0.1 pg to about 100 mg per day.