Compositions and methods for treating renal injury

Patent metadata

Field	Value
Publication number	US-2023052363-A1
Application number	US-202217892585-A
Country	US
Kind code	A1
Filing date	Aug 22, 2022
Priority date	Apr 4, 2019
Publication date	Feb 16, 2023
Grant date	—

Abstract

A method for preventing or treating renal disorder, disease, and/or injury includes administering to the subject and/or kidney a therapeutically effective amount of a 15-PGDH inhibitor.

First claim

Having described the invention, we claim:

1 . A method for preventing or treating contrast agent induced acute kidney injury (CIAKI) in a subject in need thereof, the method comprising:
administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.

2 . The method of claim 1 , wherein the amount of 15-PGDH inhibitor administered to the subject is an amount effective to induce endogenous renal PGE2 levels of the subject.

3 . The method of claim 1 , wherein the amount of 15-PGDH 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.

4 . The method of claim 1 , the amount of 15-PGDH inhibitor administered to the subject is an amount effective to reduce malondialdehyde (MDA) and NGAL levels, attenuate medulla tubular damage, reduce medulla acute tubular necrosis (ATN) and apoptosis, reduces induction of high-mobility group box 1 (HMGB1) and proinflammatory cytokines, induce renal EP4 PGE2 receptors and A2A adenosine receptors in vascular smooth muscle cells that regulate renal arterioles, increase renal cAMP, AMP, and adenosine levels, and/or inhibit induction of creatinine and KIM-1.

5 . The method of claim 1 , wherein the 15-PGDH inhibitor is administered before contrast agent administration.

6 . The method of claim 1 , wherein the 15-PGDH inhibitor is administered at a range of about 1 minute to about 72 hours before contrast agent administration.

7 . The method of claim 6 , wherein the 15-PGDH inhibitor is administered at a range of about 10 minutes to about 48 hours before contrast agent administration.

8 . The method of claim 6 , wherein the 15-PGDH inhibitor is administered at a range of about 30 minutes to about 36 hours before contrast agent administration.

9 . The method of claim 6 , wherein the 15-PGDH inhibitor is administered at time less than 2 hours before contrast agent administration.

10 . The method of claim 1 , wherein the 15-PGDH inhibitor has the following formula (V):

or a pharmaceutically acceptable salt, tatomer, or solvate thereof;
wherein n is 0-2
X 6 is independently is N or CR c
R 1 , R 6 , R 7 , and R c are the same or different each independently hydrogen or a substituted or unsubstituted group selected from C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, —Si(C 1 -C 3 alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, acyloxy, C 2 -C 24 alkoxycarbonyl, C 6 -C 20 aryloxycarbonyl, C 2 -C 24 alkylcarbonato, C 6 -C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C 1 -C 24 alkyl amino, C 5 -C 20 aryl amino, C 2 -C 24 alkylamido, C 2 -C 24 alkylamido substituted with a hydroxyl, C 6 -C 20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24 alkylsulfanyl, arylsulfanyl, C 1 -C 24 alkylsulfinyl, C 5 -C 20 arylsulfinyl, C 1 -C 24 alkylsulfonyl, C 5 -C 20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, and phosphate esters, groups incoporating amino acids, and combinations thereof, and wherein R 6 and R 7 may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl; and
U 1 is N, C—R 2 , or C—NR 3 R 4 , wherein R 2 is selected from the group consisting of a H, a lower alkyl group, O, (CH 2 ) n1 OR′ (wherein n1=1, 2, or 3), CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 X, X, (wherein X═H, F, Cl, Br, or I), CN, (C═O)—R′, (C═O)N(R′) 2 , O(CO)R′, COOR′ (wherein R′ is H or a lower alkyl group), and wherein R 1 and R 2 may be linked to form a cyclic or polycyclic ring, wherein R 3 and R 4 are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH 2 ) n1 OR′ (wherein n1=1, 2, or 3), CF 3 , CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, (wherein X═H, F, Cl, Br, or I), CN, (C═O)—R′, (C═O)N(R′) 2 , COOR′ (wherein R′ is H or a lower alkyl group), and R 3 or R 4 may be absent.

11 . The method of claim 1 , further comprising administering a contrast agent to the subject.

12 . The method of claim 11 , wherein the contrast agent is an iodinated radio contrast agent.

13 . The method of claim 11 , wherein the contrast agent comprises at least one of acetrizoate, diatrizoate, iodamide, ioglicate, iothalamate, ioxithalamate, metrizoate, metrizamide, iohexol, iopamidol, iopentol, iopromide, iodixanol, iobitridol, or ioversol.

14 . The method of claim 11 , wherein the contrast agent is iodixanol.

Assignees

• Univ Case Western Reserve

Inventors

• Markowitz Sanford
• Kim Sun-Hee
• Kim Hye Jung
• Bae Kibeom

Classifications

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/4365 Primary

  the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61P13/12

  of the kidneys · CPC title