Lonidamine analogues and treatment of polycystic kidney disease
Lonidamine derivatives can be useful in methods of treating, inhibiting, and/or preventing polycystic kidney disease (PKD). Accordingly, lonidamine derivatives can be administered in a therapeutically effective amount for inhibiting, and/or preventing polycystic kidney disease (PKD) in the subject. This can include administering a therapeutically effective amount of the lonidamine derivatives for inhibiting CFTR and/or Hsp90 or biological pathway thereof. Also, the method can include administering the lonidamine derivatives in a therapeutically effective amount for inhibiting ErbB2, Src, Raf-1, B-Raf, MEK, Cdk4, NKCC1, or combinations thereof. For example, the therapeutically effective amount of the lonidamine derivatives can be configured so as to provide a concentration in or adjacent to a kidney cell of about 0.25 uM or more or less.
1. A method for inhibiting and/or alleviating the symptoms of polycystic kidney disease (PKD) in a subject, the method comprising:
identifying a subject in need of treatment of PKD;
administering to the subject a compound according to Formula I:
wherein R 1 is propionic acid, carboxyl, acryl, or carboxylic acid hydrazide;
wherein R 2 is halogen, alcohol, alkoxy, aralkyl, cycloalkyl, haloalkyl, haloalkoxy, amino, or carboxyl;
wherein X and Y are the same or different from each other and are halogen or lower alkyl;
wherein Z 1 , Z 2 , Z 3 , and Z 4 are carbon; and
pharmaceutically acceptable salts and esters thereof.
2. A method as in claim 1 , wherein R 2 is a trihaloalkyl at the 6-position.
3. A method as in claim 1 , wherein the compound is selected from the group consisting of:
3-[1-(2,4-dichlorobenzyl)-6-trifluoromethyl-1H-indazol-3-yl]-acrylic acid;
6-chloro-1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid hydrazide;
1-(2,4-dichlorobenzyl)-6-fluoro-1H-indazole-3-carboxylic acid methyl ester;
6-fluoro-1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid hydrazide;
3-[1-(2,4-dichlorobenzyl)-6-fluoro-1H-indazol-3-yl]-acrylic acid;
3-[1-(2,4-dichlorobenzyl)-6-chloro-1H-indazol-3-yl]-acrylic acid;
3-[1-(2,4-dichlorobenzyl)-6-trifluoromethoxy-1H-indazol-3-yl]acrylic acid;
3-[1-(2,4-dichlorobenzyl)-6-chloro-1H-indazol-3-yl]-propionic acid;
3-[1-(2,4-dichlorobenzyl)-6-trifluoromethyl-1H-indazol-3-yl]-propionic acid; and
pharmaceutically acceptable salts and esters thereof.
4. A method as in claim 1 , wherein the compound is selected from the group consisting of:
gamendazole;
3-[1-(2,4-dichlorobenzyl)-6-trifluoromethyl-1H-indazol-3-yl]-propionic acid (JWS-2-72 or H2-gamendazole);
3-[1-(2,4-dichlorobenzyl)-6-methyl-1H-indazol-3-yl]acrylic acid (TH 2-192);
1-(2,4-dichlorobenzyl)-6-methyl-1H-indazole-3-carboxylic acid (TH 2-178);
3-[1-(2,4-dichlorobenzyl)-6-chloro-1H-indazol-3-yl]-acrylic acid (JWS 1-190);
1-(2-chloro-4-fluorobenzyl)-6-chloro-1H-indazole-3-carboxylic acid hydrazide (JWS 2-22);
1-(2,4-difluorobenzyl)-6-chloro-1H-indazole-3-carboxylic acid hydrazide (JWS 1-282); and
pharmaceutically acceptable salts and esters thereof.
5. A method as in claim 1 , wherein R 1 is a carboxylic acid hydrazide.
6. A method as in claim 1 , wherein the compound is administered in a therapeutically effective amount for inhibiting polycystic kidney disease (PKD) in the subject.
7. A method as in claim 1 , wherein the compound is administered in a therapeutically effective amount for inhibiting CFTR and/or Hsp90 or biological pathway thereof.
8. A method as in claim 7 , wherein the compound is administered in a therapeutically effective amount for inhibiting ErbB2, Src, Raf-1, B-Raf, MEK, Cdk4, NKCC1, or combinations thereof.
9. A method for inhibiting cystic fibrosis transmembrane conductance regulator (CFTR), the method comprising:
identifying a subject in need of treatment of PKD and administering a compound according to Formula I:
wherein R 1 is propionic acid, carboxyl, acryl, or carboxylic acid hydrazide;
wherein R 2 is halogen, alcohol, alkoxy, aralkyl, cycloalkyl, haloalkyl, haloalkoxy, amino, or carboxyl;
wherein X and Y are the same or different from each other and are halogen or lower alkyl;
wherein Z 1 , Z 2 , Z 3 , and Z 4 are carbon; and
pharmaceutically acceptable salts and esters thereof.
10. A method as in claim 9 , wherein R 2 is a trihaloalkyl at the 6-position.
11. A method as in claim 9 , wherein the compound is selected from the group consisting of:
3-[1-(2,4-dichlorobenzyl)-6-trifluoromethyl-1H-indazol-3-yl]-acrylic acid;
6-chloro-1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid hydrazide;
1-(2,4-dichlorobenzyl)-6-fluoro-1H-indazole-3-carboxylic acid methyl ester;
6-fluoro-1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid hydrazide;
3-[1-(2,4-dichlorobenzyl)-6-fluoro-1H-indazol-3-yl]-acrylic acid;
3-[1-(2,4-dichlorobenzyl)-6-chloro-1H-indazol-3-yl]-acrylic acid;
3-[1-(2,4-dichlorobenzyl)-6-trifluoromethoxy-1H-indazol-3-yl]acrylic acid;
3-[1-(2,4-dichlorobenzyl)-6-chloro-1H-indazol-3-yl]-propionic acid;
3-[1-(2,4-dichlorobenzyl)-6-trifluoromethyl-1H-indazol-3-yl]-propionic acid; and
pharmaceutically acceptable salts and esters thereof.
12. A method as in claim 9 , wherein the compound is selected from the group consisting of:
gamendazole;
3-[1-(2,4-dichlorobenzyl)-6-trifluoromethyl-1H-indazol-3-yl]-propionic acid (JWS-2-72 or H2-gamendazole);
3-[1-(2,4-dichlorobenzyl)-6-methyl-1H-indazol-3-yl]acrylic acid (TH 2-192);
1-(2,4-dichlorobenzyl)-6-methyl-1H-indazole-3-carboxylic acid (TH 2-178);
3-[1-(2,4-dichlorobenzyl)-6-chloro-1H-indazol-3-yl]-acrylic acid (JWS 1-190);
1-(2-chloro-4-fluorobenzyl)-6-chloro-1H-indazole-3-carboxylic acid hydrazide (JWS 2-22);
1-(2,4-difluorobenzyl)-6-chloro-1H-indazole-3-carboxylic acid hydrazide (JWS 1-282); and
and pharmaceutically acceptable salts and esters thereof.