Compounds and uses thereof
The present invention provides novel compounds of any one of Formulae (I)-(IV), and pharmaceutical compositions thereof. Also provided are particles (e.g., nanoparticles) comprising compounds of any one of Formulae (I)-(IV) and pharmaceutical compositions thereof that are mucus penetrating. The invention also provides methods and kits for using the inventive compounds, and pharmaceutical compositions thereof, for treating and/or preventing diseases associated with abnormal or pathological angiogenesis and/or aberrant signaling of a growth factor signaling pathway (e.g., vascular endothelial growth factor (VEGF)), such as proliferative diseases (e.g., cancers, benign neoplasms, inflammatory diseases, autoimmune diseases) and ocular diseases (e.g., macular degeneration, glaucoma, diabetic retinopathy, retinoblastoma, edema, uveitis, dry eye, blepharitis, and post-surgical inflammation) in a subject in need thereof.
1. A compound of the following formula:
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
3. A mucus-penetrating pharmaceutical composition, comprising:
a plurality of coated particles, comprising:
a core particle comprising a compound of claim 1 and
a mucus penetration-enhancing coating comprising a surface-altering agent surrounding the core particle,
wherein the surface-altering agent comprises one or more of the following components:
a) a triblock copolymer comprising a hydrophilic block-hydrophobic block-hydrophilic block configuration, wherein the hydrophobic block has a molecular weight of at least about 2 kDa, and the hydrophilic blocks constitute at least about 15 wt % of the triblock copolymer, wherein the hydrophobic block associates with the surface of the core particle, and wherein the hydrophilic block is present at the surface of the coated particle and renders the coated particle hydrophilic,
b) a synthetic polymer having pendant hydroxyl groups on the backbone of the polymer, the polymer having a molecular weight of at least about 1 kDa and less than or equal to about 1000 kDa, wherein the polymer is at least about 30% hydrolyzed and less than about 95% hydrolyzed, or
c) a polysorbate,
an pharmaceutically acceptable carrier, additive, or diluent.
4. The pharmaceutical composition of claim 3 , wherein the core comprises
5. The pharmaceutical composition of claim 3 , wherein the surface-altering agent is present on the surfaces of the coated particles at a density of at least about 0.1 molecules per nanometer squared.
6. The pharmaceutical composition of claim 3 , wherein the surface-altering agent is covalently attached to the core particles.
7. The pharmaceutical composition of claim 3 , wherein the surface-altering agent is non-covalently adsorbed to the core particles.
8. The pharmaceutical composition of claim 3 , wherein the surface-altering agent comprises the triblock copolymer.
9. The pharmaceutical composition of claim 8 , wherein the surface-altering agent comprises the triblock copolymer, wherein the hydrophilic blocks of the triblock copolymer constitute at least about 30 wt % of the triblock polymer and less than or equal to about 80 wt % of the triblock copolymer.
10. The pharmaceutical composition of claim 9 , wherein the hydrophobic block portion of the triblock copolymer has a molecular weight of about 3 kDa to about 8 kDa.
11. The pharmaceutical composition of claim 8 , wherein the triblock copolymer is poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide).
12. The pharmaceutical composition of claim 3 , wherein the surface-altering agent has a molecular weight of at least about 4 kDa.
13. The pharmaceutical composition of claim 3 , wherein the linear polymer having pendant hydroxyl groups on the backbone of the polymer is a poly(vinyl alcohol).
14. The pharmaceutical composition of claim 13 , wherein the poly(vinyl alcohol) is about 70% to about 94% hydrolyzed.
15. The pharmaceutical composition of claim 3 , wherein the compound is encapsulated in a polymer, a lipid, a protein, or a combination thereof.
16. The pharmaceutical composition of claim 3 , wherein the compound comprises at least about 80 wt % of the core particle.
17. The pharmaceutical composition of claim 3 , wherein the coated particles have an average size of about 10 nm to about 1 μm.
18. The pharmaceutical composition of claim 3 , wherein the polydispersity index of the composition is less than or equal to about 0.5.
19. The pharmaceutical composition of claim 3 , wherein the pharmaceutical composition is suitable for topical administration to the eye.
20. The pharmaceutical composition of claim 3 , wherein the pharmaceutical composition is suitable for direct injection into the eye.
21. The pharmaceutical composition of claim 3 , wherein the ophthalmically acceptable carrier, additive, or diluent comprises glycerin.
22. A method of treating an ocular disease in a subject in need thereof comprising:
administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound, or a mucus-penetrating pharmaceutical composition comprising the compound.
23. The method according to claim 22 , wherein the ocular disease is macular degeneration, diabetic retinopathy, retinoblastoma, edema, diabetic macular edema, retinal vein occlusion, age-related macular degeneration, or corneal neovascularization.
24. The method according to claim 22 , wherein the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered orally or administered topically to the eye.
25. A method of inhibiting growth factor signaling comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound, or a mucus-penetrating pharmaceutical composition comprising the compound, and optionally a pharmaceutically acceptable excipient.