Tie-2 activators targeting the Schlemm's canal
Disclosed herein are compounds effective for activation of Tie-2 and inhibition of HPTP-beta. The compounds can provide effective therapy for eye conditions, for example, intraocular pressure, ocular hypertension, and glaucoma.
1. A method for modulating fluid outflow in an eye of a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a Tie-2 activator, wherein administration of the Tie-2 activator in the subject modulates the fluid outflow by at least 20% as compared to absence of administration.
2. The method of claim 1 , wherein the fluid outflow that is modulated by the administration is outflow of aqueous humor.
3. The method of claim 1 , wherein the administration reduces intraocular pressure in the eye of the subject by at least 15%.
4. The method of claim 1 , wherein Tie-2 is activated in a Schlemm's canal of the subject upon the administration of the Tie-2 activator.
5. The method of claim 1 , wherein the Tie-2 activator binds to HPTPβ in a Schlemm's canal of the subject.
6. The method of claim 1 , wherein the Tie-2 activator inhibits HPTPβ in a Schlemm's canal of the subject.
7. The method of claim 1 , wherein the modulating is an increase in the fluid outflow in the eye of the subject.
8. The method of claim 7 , wherein the fluid outflow is increased by at least 25%.
9. The method of claim 7 , wherein the fluid outflow is increased by 2 nL/min/mmHg to 4 nL/min/mmHg.
10. The method of claim 1 , wherein the administration is topical.
11. The method of claim 1 , wherein the administration is topical to the eye of the subject.
12. The method of claim 1 , wherein the administration is subcutaneous.
13. The method of claim 1 , wherein the Tie-2 activator is administered to the subject as a unit dosage form.
14. The method of claim 13 , wherein the unit dosage form is formulated as a drop.
15. The method of claim 14 , wherein the drop contains an amount of the Tie-2 activator that is from 1% to 5% of the unit dosage form by mass.
16. The method of claim 14 , wherein the drop further comprises a pharmaceutically-acceptable excipient.
17. The method of claim 16 , wherein the pharmaceutically-acceptable excipient is a dextrose.
18. The method of claim 16 , wherein the pharmaceutically-acceptable excipient is a cyclodextrin.
19. The method of claim 1 , wherein the Tie-2 activator is a compound of the formula:
wherein:
Aryl 1 is an aryl group which is substituted or unsubstituted; Aryl 2 is an aryl group which is substituted or unsubstituted; X is alkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, an amide linkage, an ester linkage, a thioether linkage, a carbamate linkage, a carbonate linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond; and
Y is H, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO 2 R g , or NHCOR g , any of which is substituted or unsubstituted, or
wherein:
L 2 is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L 2 is bound forms an amide linkage, a carbamate linkage, or a sulfonamide linkage, or a chemical bond, or together with any of R a , R b , R c , and R d forms a ring that is substituted or unsubstituted;
R a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L 2 , R b , R c , and R d forms a ring that is substituted or unsubstituted;
R b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L 2 , R a , R c , and R d forms a ring that is substituted or unsubstituted;
R c is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a , R b , and R d forms a ring that is substituted or unsubstituted;
R d is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a , R b , and R c forms a ring that is substituted or unsubstituted; and
R g is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted,
or a pharmaceutically-acceptable salt thereof.
20. The method of claim 19 , wherein:
Aryl 1 is substituted or unsubstituted phenyl;
Aryl 2 is substituted or unsubstituted heteroaryl; and
X is alkylene.
21. The method of claim 20 , wherein:
Aryl 1 is substituted phenyl;
Aryl 2 is substituted heteroaryl; and
X is methylene.
22. The method of claim 21 , wherein the compound that activates Tie-2 is a compound of the formula:
wherein
Aryl 1 is para-substituted phenyl;
Aryl 2 is substituted heteroaryl;
X is methylene;
L 2 is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L 2 is bound forms an amide linkage, a carbamate linkage, or a sulfonamide linkage, or a chemical bond;
R a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted;
R b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted;
R c is H or alkyl which is substituted or unsubstituted; and
R d is H or alkyl which is substituted or unsubstituted.
23. The method of claim 22 , wherein:
Aryl 1 is para-substituted phenyl;
Aryl 2 is a substituted thiazole moiety;
X is methylene;
L 2 together with the nitrogen atom to which L 2 is bound forms a carbamate linkage;
R a is alkyl, which is substituted or unsubstituted;
R b is arylalkyl, which is substituted or unsubstituted;
R c is H; and
R d is H.
24. The method of claim 23 , wherein Aryl 2 is:
wherein:
R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and
R f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.
25. The method of claim 19 , wherein the compound is:
26. The method of claim 19 , wherein the compound is:
27. The method of claim 24 , wherein:
Aryl 1 is 4-phenylsulfamic acid;
R a is alkyl, which is substituted or unsubstituted;
R b is arylalkyl, which is substituted or unsubstituted;
R e is H; and
R f is alkyl.
28. The method of claim 19 , wherein the compound is:
29. The method of claim 19 , wherein the compound is:
30. The method of claim 23 , wherein Aryl 2 is:
wherein:
R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and
R f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.
31. The method of claim 19 , wherein the compound is:
32. The method of claim 19 , wherein the compound is:
33. The method of claim 19 , wherein the compound is:
34. The method of claim 19 , wherein the compound is:
35. A method for modulating fluid outflow in an eye of a subject in need thereof, the method comprising topically administering to the eye of the subject a therapeutically-effective amount of a Tie-2 activator in a unit dosage form, wherein administration of the Tie-2 activator in the subject modulates the fluid outflow by at least 20% as compared to absence of administration, wherein the Tie-2 activator is a compound of the formula:
or a pharmaceutically-acceptable salt thereof, wherein the unit dosage form comprises 10 μM of the Tie-2 activator.
36. The method of claim 1 , wherein the administration modulates an outflow facility of the eye of the subject.
37. The method of claim 1 , wherein the administration increases an outflow facility of the eye of the subject.
38. The method of claim 1 , wherein the administration modulates outflow of aqueous humor in the eye of the subject.
39. The method of claim 1 , wherein the administration increases outflow of aqueous humor in the eye of the subject.