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US 2024/0366568 A1Published application
Compositions and methods for treating tissue injury
AssigneeCase Western Reserve University
InventorJonathan S. Stamler
Life of this patent
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Abstract
A method for preventing or treating a tissue injury and/or promoting tissue repair in a subject in need thereof, includes administering to the subject a therapeutically effective amount of an ADH inhibitor, AKR inhibitor, SCoR inhibitor, and/or PKM2 inhibitor.
Claims24
1:
- A method for preventing or treating acute kidney injury in a subject in need thereof, the method comprising:
- administering to the subject a therapeutically effective amount of a selective or partially selective AKR1A1 inhibitor.
(canceled)
(canceled)
4:
- The method of claim 1, wherein the method prevents or treats acute kidney injury associated with a renal ischemia reperfusion injury or a nephrotic acute kidney injury.
5:
- The method of claim 4, wherein the amount of the selective or partially selective AKR1A1 inhibitor administered to the subject is an amount effective to induce renal vasodilatation, enhance resistance to hypoxia, improve renal hemodynamics, decrease renal oxidative stress, reduce renal inflammation, and/or preserve renal function.
6:
- The method of claim 4, wherein the selective or partially selective AKR1A1 inhibitor is administered before and/or after the acute kidney injury.
(canceled)
8:
- The method of claim 1, wherein the selective or partially selective AKR1A1 inhibitor is administered at least about 2 hours before and/or at least about 30 minutes after the acute kidney injury.
(canceled)
10:
- The method of claim 1, wherein the acute kidney injury is associated with a transplant in the subject.
11:
- The method of claim 10, wherein said transplant is a kidney transplant.
12:
- The method of claim 1, wherein said acute kidney injury is associated with cardiovascular surgery or sepsis.
13:
- The method of claim 1, wherein the selective or partially selective AKR1A1 inhibitor is administered at an amount(s) effective to promote S-nitrosylation of proteins in the subject, wherein the the selective or partially selective AKR1A1 inhibitor is not an ADH3 inhibitor.
(canceled)
15:
- The method of claim 1, wherein the selective or partially selective AKR1A1 inhibitor includes an analogue of imirestat.
16:
- The method of claim 15, wherein the analogue of imirestat includes a compound selected from:
- R1, R2, R3, R4, R5, R6, and R7 are the same or different and are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, carbamido, cyano, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, sulfanamido, imino, alkylimino, arylimino, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, and combinations thereof;
- and pharmaceutically acceptable salts thereof, and wherein the compound is not imirestat.
17:
- The method of claim 16, wherein R1, R2, R3, R4, R5, R6, and R7 are the same or different are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, —OH, carboxyl, alkylene carboxyl, alkylene cycloalkyl, alkylene heterocyclyl, alkylene heteroaryl, alkylene-C(O)N(R8)m, —O-alkylene-carboxyl, —O-arylene-carboxyl, —O— alkylene-arylene, —O-alkylene-heteroaryl, —O-alkylene-heterocyclyl, carboxyl, alklyne carboxyl, —O-alkylene-N(R8)2, —N(R8)2, —N(R8)(alkylene-OH), —C(O)N(R1)m, —C(O)N(R8)(alkylene-OH), —C(O)N(R8)(alkylene carboxyl), —C(O)N(R8)S(O)m-alkyl, —C(O)-alkyl, —C(O)O-alkyl, alkoxy, or —S(O)m-alkyl, each R8 is independently, H, alkyl, -alkylene-OH optionally substituted with —OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, —C(O)-alkyl, —C(O)O-alkyl, -alkylene-COOH, or —S(O)m-alkyl;
- or alternatively, two R8 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R9;
- and
- R9 is halogen, alkyl, or alkoxy, m is 0, 1, or 2.
1 more element
18:
- The method of claim 15, wherein the the analogue of imirestat includes a compound selected from:
- and pharmaceutically acceptable salts thereof.
19:
- The method of claim 15, wherein the AKR1A1 inhibitor has a selectivity for AKR1A1 versus AKR1B1≥2 times.
(canceled)
(canceled)
22:
- The method of claim 1, further comprising administering nicotinamide adenine dinucleotide (NAD+) and/or a NAD+ precursor in combination with the selective or partially selective AKR1A1 inhibitor.
23:
- The method of claim 22, wherein the NAD+ precursor is selected from the group consisting of tryptophan, nicotinic acid, nicotinic acid riboside, nicotinamide riboside (NR), and nicotinamide (NAM).
24:
- The method of claim 1, wherein the selective or partially selective AKR1A1 inhibitor is selected from:
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.