Use of small molecule inhibitors targeting EYA tyrosine phosphatase
Inhibitors of EYA tyrosine phosphatase are provided herein, as well as pharmaceutical compositions and methods relating thereto.
1. A method of treating an ocular disorder in an individual, comprising:
selecting or identifying an individual suffering from an ocular disorder selected from the group consisting of proliferative retinopathy, retinopathy of prematurity, diabetic retinopathy, age related macular degeneration, retinal vasculitis, exudative vitreoretinopathy, tumor angiogenesis, hemangiomas or tumor metastasis; and
administering to the individual a compound selected from the group of compounds having the structure of Formula III:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl are each optionally substituted with one or more R 1A ;
R 2 is selected from the group consisting of H (hydrogen), halo, hydroxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, and C 1-6 alkyl substituted with one or more hydroxy;
R 3 is selected from the group consisting of halo, hydroxy, O-carbamyl, N-carbamyl, C-amido, S-sulfonamido, N-sulfonamido, C-carboxy, amino, and C 1-6 alkyl substituted with one or more hydroxy;
R 4 is selected from the group consisting of H (hydrogen), halo, C 1-6 alkyl optionally substituted with up to 5 fluoro and C 1-6 alkoxy optionally substituted with up to 5 fluoro;
each R 1A is independently selected from the group consisting of hydroxy, halo, C 1-6 alkyl substituted with up to 5 fluoro, and C 1-6 alkoxy optionally substituted with up to 5 fluoro;
each R 2A is independently selected from the group consisting of H (hydrogen), halo, hydroxy, O-carbamyl, N-carbamyl, C-amido, S-sulfonamido, N-sulfonamido, C-carboxy, amino, C 2-6 alkenyl, C 2-6 alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, C 1-6 alkyl substituted with one or more hydroxyl, and C 1-6 alkyl optionally substituted with up to 5 fluoro; and
Y 1 is O (oxygen), or S (sulfur),
wherein the compound is administered to the individual in an amount effective to inhibit an EYA tyrosine phosphatase but below the level effective to inhibit a cysteine catalysis-based tyrosine phosphatase.
2. The method of claim 1 , wherein Y 1 is O (oxygen).
3. The method of claim 1 , wherein each R 2A is independently selected from the group consisting of H (hydrogen), and C 1-6 alkyl optionally substituted with up to 5 fluoro.
4. The method of claim 1 ,
wherein:
R 4 is selected from the group consisting of fluoro, chloro, bromo, methyl, —CF 3 , —OCH 3 , and —OCF 3 .
5. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 ,
wherein:
R 2 is selected from the group consisting of fluoro, chloro, bromo, and iodo.
8. The method of claim 1 ,
wherein:
R 4 is selected from the group consisting of fluoro, chloro, bromo, and iodo.
9. The method of claim 1 ,
wherein:
R 1 is substituted C 1-6 alkyl, and R 1A is hydroxy.
10. The method of claim 1 ,
wherein the compound is administered to the individual in an amount effective to specifically inhibit an EYA tyrosine phosphatase without inhibiting PTP-1B tyrosine phosphatase.
11. The method of claim 10 , wherein the amount effective to specifically inhibit an EYA tyrosine phosphatase without inhibiting PTP-1B tyrosine phosphatase is 17 μM or less.