METHODS OF TREATING DIABETIC NEPHROPATHY USING HPTPB INHIBITORS
Disclosed herein are compounds effective for activation of Tie-2 and inhibition of HPTP-beta. The compounds can provide effective therapy for conditions associated with diabetic nephropathy, for example, diabetic nephropathy resulting from hyperglycemia, kidney hyperfiltration, renal injury, glycation products, and cytokine activation.
1 . A method of treating nephropathy in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound that activates Tie-2.
2 . The method of claim 1 , wherein the compound has 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, tautomer, or zwitterion thereof.
3 . The method of claim 2 , wherein:
Aryl 1 is substituted or unsubstituted phenyl;
Aryl 2 is substituted or unsubstituted heteroaryl; and
X is alkylene.
4 . The method of claim 3 , wherein:
Aryl 1 is substituted phenyl;
Aryl 2 is substituted heteroaryl; and
X is methylene.
5 . The method of claim 3 , 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.
6 . The method of claim 5 , wherein:
Aryl 2 is a substituted thiazole moiety;
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.
7 . The method of claim 6 , 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.
8 . The method of claim 7 , wherein:
R e is H, OH, F, Cl, Br, I, alkyl, an alkoxy 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, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.
9 . The method of claim 8 , wherein:
R e is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted; and
R f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted.
10 . The method of claim 9 , 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 heteroaryl.
11 . The method of claim 7 , 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.
12 . The method of claim 2 , wherein the compound is:
13 . The method of claim 2 , wherein the compound is:
14 . The method of claim 2 , wherein the compound is:
15 . The method of claim 2 , wherein the compound is:
16 . The method of claim 6 , 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.
17 . The method of claim 16 , wherein:
R e is H, OH, F, Cl, Br, I, alkyl, an alkoxy 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, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.
18 . The method of claim 17 , wherein:
R e is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted; and
R f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted.
19 . The method of claim 18 , 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 heteroaryl.
20 . The method of claim 2 , wherein the compound is:
21 . The method of claim 2 , wherein the compound is:
22 . The method of claim 1 , wherein the nephropathy is diabetic nephropathy.
23 . The method of claim 1 , wherein the therapeutically-effective amount is from about 0.1 mg to about 100 mg.
24 . The method of claim 23 , wherein the therapeutically-effective amount is from about 0.5 mg to about 30 mg.
25 . The method of claim 1 , wherein the compound is administered subcutaneously.
26 . The method of claim 1 , wherein the administering reduces a urine albumin-to-creatinine ratio by at least about 20% in the subject.