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US-12616681-B2 - Compositions and methods for treating renal injury

US12616681B2US 12616681 B2US12616681 B2US 12616681B2US-12616681-B2

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.

Inventors

  • Sanford Markowitz
  • Sun-Hee Kim
  • Hye Jung Kim
  • Ki Beom Bae

Assignees

  • CASE WESTERN RESERVE UNIVERSITY
  • INJE INDUSTRY ACADEMIC COOPERATION FOUNDATION

Dates

Publication Date
20260505
Application Date
20220822

Claims (12)

  1. 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. 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. 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. 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. 5 . The method of claim 1 , wherein the 15-PGDH inhibitor is administered before contrast agent administration.
  6. 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. 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. 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. 9 . The method of claim 6 , wherein the 15-PGDH inhibitor is administered at time less than 2 hours before contrast agent administration.
  10. 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 incorporating 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. 11 . The method of claim 1 , wherein the contrast agent is an iodinated radio contrast agent.
  12. 12 . 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, or ioversol.

Description

RELATED APPLICATION This application is a Continuation-in-Part of PCT/US2021/019084, filed Feb. 22, 2021, which claims priority from U.S. Provisional Application No. 62/979,813 filed Feb. 21, 2020, and is Continuation-in-Part of PCT/US2019/025812, filed Apr. 4, 2019, the subject matter of which are incorporated herein by reference in their entirety. GOVERNMENT FUNDING This invention was made with government support under grant CA197442 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Acute kidney injury (AKI) is an important clinical problem associated with high rates of morbidity and mortality (1.7 million deaths annually). Considerable effort has been directed toward the development of preventive strategies for AKI using various agents and animal models. Despite advances in prevention strategies, no specific treatment for AKI has yet been developed. The main causes of AKI are hypoxia and oxidative stress due to renal ischemic reperfusion injury (IRI). During periods of transient reduction in renal blood flow (RBF), an insufficient oxygen supply can cause energy impairment (ATP depletion) in the renal outer medulla, resulting in the injury and death of the tubular epithelial cells due to acute tubular necrosis (ATN) and apoptosis. The inflammation due to oxygen-free radicals after reperfusion leads to the extension phase of ischemic AKI. Resistance to hypoxia and the reduction of oxidative stress are treatment targets for ischemic AKI. SUMMARY Embodiments described herein relate to compositions and methods of preventing, treating, or reducing the severity of a renal disorder, disease, and/or injury. It was found that administration of a 15-PGDH inhibitor to a subject prior to and/or after renal injury can induce renal vasodilation, and enhance resistance to hypoxia resulting in a prophylactic and protective effect against renal injury. These benefits can be associated with a prophylactic use of as little as a single dose of a 15-PGDH inhibitor. Administration of a 15-PGDH inhibitor to a subject having or at risk of a renal injury improved renal hemodynamics, decreased induction of oxidative stress, reduced induction of inflammation, attenuated multiple markers of renal damage and preserved renal function. Moreover, administration of a 15-PGDH inhibitor before and/or after administration of a contrast media was found to prevent and/or treat contrast-induced acute kidney injury (CIAKI). Accordingly, in some embodiments, compositions and methods of inhibiting 15-PDGH activity can be used to prevent, treat, or reduce the severity of a renal disorder, disease, and/or injury in a subject and/or kidney of a subject in need thereof. Examples of renal disorders, diseases, and/or injuries that can be treated include hypotensive injury to the kidney; hypertensive renal disease; diabetic renal disease and diabetic nephropathy; renal disease from vasculitis and autoimmune diseases, including but not limited to lupus erythematosis, polyarteritis, Wegeners' Granulomatosis, and mixed connective tissue disease; ischemic renal injury; acute renal failure; chronic renal failure; glomerulonephritis; nephrotic syndrome; acute tubular necrosis; nephrosclerosis; gomerulosclerosis; minimal change disease; idiopathic membranous nephropathy; membranoproliferative glomerulonephritis; Berger's disease; mesangial proliferative glomerulonephritis; chronic glomerulonephritis; focal glomerulosclerosis; renal effects of Sjogren's syndrome; renal effects of scleroderma; interstitial nephritis; and renal injury to a kidney donor, transplant recipient, and/or transplanted kidney following kidney transplant. In other embodiments, the 15-PGDH inhibitor can prevent or treat acute kidney injury (AKI) associated with renal ischemia reperfusion injury (IRI). In some embodiments, the amount of 15-PGDH inhibitor administered to a subject can be an amount effective to induce endogenous renal PGE2 levels of the subject. In other embodiments, the amount of 15-PGDH inhibitor administered to a subject can be an amount effective to induce renal vasodilatation, enhance resistance to hypoxia, improve renal hemodynamics, decrease renal oxidative stress, reduce renal inflammation, and preserve renal function. In other embodiments, the amount of 15-PGDH inhibitor administered to a subject is an amount effective to reduce malondialdehyde (MDA) and NGAL levels, attenuate medulla tubular damage, reduce medulla acute tubular necrosis (ATN) and apoptosis, reduce 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. In other embodiments, the 15-PGDH inhibitor can be administered to a subject before a renal injury. For example, the 15-PGDH inhibitor can be administer