IP Library › Granted Patent US 12,478,594
Granted Patent B2
US 12,478,594 · App. 17/614,191 · Granted Nov 25, 2025

Methods of treatment of kidney injury associated with infection or trauma

Inventors: John A. Kellum (Pittsburgh, PA); Neil Hukriede (Allison Park, PA); Xiaoyan Wen (Pittsburgh, PA)
Assignee: University of Pittsburgh—Of the Commonwealth System of Higher Education
A61K31/167A61P13/12
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,478,594
App. No.
17/614,191
Granted
Nov 25, 2025
Kind
B2
Abstract

Provided herein is a method of treating kidney injury associated with trauma or infection, such as in sepsis-associated acute kidney injury in a patient including administering to the patient an amount of a histone deacetylase inhibitor effective to treat kidney injury associated with trauma or infection in a patient, beginning either between greater than 48 hours and two weeks after the insult leading to the trauma or infection, or after initial inflammation following the trauma or infection has decreased, and prior to development of irreversible fibrosis in the kidney.

Claims (15)

1 . A method of treating a sepsis-induced kidney injury in a patient, comprising administering to the patient an amount of a selective histone deacetylase inhibitor effective to treat a sepsis-induced kidney injury in a patient, beginning after initial inflammation following an insult leading to the sepsis has decreased, and prior to development of irreversible fibrosis in the kidney.

2 . The method of claim 1 , wherein the histone deacetylase inhibitor is administered starting from 96 hours to one week after the insult leading to the sepsis.

3 . The method of claim 1 , wherein the selective histone deacetylase inhibitor is N-(2-hydroxyphenyl)-4-(phenylsulfanyl) butanamide (UPHD-186).

4 . The method of claim 1 , wherein the selective histone deacetylase inhibitor is methyl 4-(phenylsulfanyl) butanoate (UPHD-25).

5 . The method of claim 1 , wherein the selective histone deacetylase inhibitor is 4-[(4-fluorophenyl) sulfanyl]-N-hydroxybutanamide (UPHD-29), N-hydroxy-4-[(4-methylphenyl) sulfanyl] butanamide (UPHD-28), 5-[(4-fluorophenyl) sulfanyl]-N-hydroxypentanamide (UPHD-34), 6-[(4-fluorophenyl) sulfanyl]-N-hydroxyhexanamide (UPHD-51), 4-{2 [(4-fluorophenyl) sulfanyl] ethyl}-N-hydroxybenzamide (UPHD-67), methyl 4-[(4-fluorophenyl) sulfanyl] butanoate (UPHD-30), methyl 4-[(4-methoxyphenyl) sulfanyl] butanoate (UPHD-22), methyl 6-(phenylsulfanyl) hexanoate (UPHD-47), methyl 6-[(4-fluorophenyl) sulfanyl] hexanoate (UPHD-48), N-(2-aminophenyl)-6-(phenylsulfanyl) hexanamide (UPHD-49), N-(2-aminophenyl)-6-[(4-fluorphenyl) sulfanyl] hexanamide (UPHD-53), 6-[(4-fluorophenyl) sulfanyl]-N-(2-hydroxyphenyl) hexanamide (UPHD-77), methyl 6-[4-(methylsulfanyl) phenoxy] hexanoate (UPHD-146), methyl 6-(4-methanesulfonylphenoxy) hexanoate (UPHD-149), methyl 4-({5-[(2-hydroxyphenyl) carbamoyl] pentyl} sulfanyl) benzoate (UPHD-150), methyl 4-({5-[(2-aminophenyl) carbamoyl] pentyl} sulfanyl) benzoate (UPHD-151), methyl 3-[(6-methoxy-6-oxohexyl) sulfanyl] benzoate (UPHD-152), methyl 2-[(6-methoxy-6-oxohexyl) sulfanyl] benzoate (UPHD-153), methyl 6-[(3-hydroxyphenyl) sulfanyl] hexanoate (UPHD-154), N-(2-hydroxyphenyl)-6-[4-(methylsulfanyl) phenoxy] hexanamide (UPHD-155), N-(2-aminophenyl)-6-[4-(methylsulfanyl) phenoxy] hexanamide (UPHD-156), methyl 6-[(2-hydroxyphenyl) sulfanyl] hexanoate (UPHD-158), methyl 2-({5-[(2-hydroxyphenyl) carbamoyl] pentyl} sulfanyl) benzoate (UPHD-161), methyl 6-(4-methanesulfinylphenoxy) hexanoate (UPHD-162), methyl]6-[(4-carbamoylphenyl) sulfanyl] hexanoate (UPHD-168), methyl 2-({5-[(2-aminophenyl) carbamoyl] pentyl} sulfanyl) benzoate (UPHD-170), methyl 6-{[4-(methylcarbamoyl) phenyl] sulfanyl} hexanoate (UPHD-171), 6-{[3-(methylcarbamoyl) phenyl] sulfanyl} hexanoate (UPHD-174), 4-({5-[(2-aminophenyl) carbamoyl] pentyl} sulfanyl)-N-methylbenzamide (UPHD-175), 4-({5-[(2-hydroxyphenyl) carbamoyl] pentyl} sulfanyl)-N-methylbenzamide (UPHD-176), methyl 5-(benzylsulfanyl) pentanoate (UPHD-178), methyl 4-[(2-phenylethyl) sulfanyl] butanoate (UPHD-179), methyl 5-{[(4-methoxyphenyl) methyl] sulfanyl} pentanoate (UPHD-180), 3-({5-[(2-(UPHD-181), 3-({5-[(2-hydroxyphenyl) carbamoyl] pentyl} sulfanyl)-N-methylbenzamide aminophenyl) carbamoyl] pentyl} sulfanyl)-N-methylbenzamide (UPHD-185), N-(2-aminophenyl)-5-(benzysulfanyl) pentanamide (UPHD-188), N-(2-aminophenyl)-5-{[(4-methoxyphenyl) methyl] sulfanyl} pentanamide (UPHD-189), N-(2-aminophenyl)-4-[(2-phenylethyl) sulfanyl] butanamide (UPHD-190), 5-(benzylsulfanyl)-N-(2-hydroxyphenyl) pentanamide (UPHD-191), N-(2-hydroxyphenyl)-5-{[(4-methoxyphenyl) methyl] sulfanyl} pentanamide (UPHD-192), N-(2-hydroxyphenyl)-4-[(2-(UPHD-193), N-hydroxy-5-{[(4-phenylethyl) sulfanyl] butanamide methoxyphenyl) methyl] sulfanyl} pentanamide (UPHD-194), 5-(benzylsulfanyl)-N-hydroxypentanamide (UPHD-195), N-hydroxy-4-[(2-phenylethyl) sulfanyl] butanamide (UPHD-196), methyl 6-(4-methanesulfonylbenzenesulfonyl) hexanoate (UPHD-197), N-(3-hydroxy-6-methylpyridin-2-yl)-4-(phenylsulfanyl) butanamide methyl 6-(UPHD-198), [methoxy (phenyl) phosphoryl] hexanoate (UPHD-199), methyl 5-phenylmethanesulfinylpentanoate (UPHD-201), methyl 6 {[2-(methylcarbamoyl) phenyl] sulfanyl} hexanoate (UPHD-202), methyl 4-[methoxy (phenyl) phosphoryl′butanoate (UPHD-203), N-(3-hydroxy-6-methylpyridin-2-yl)-6-(phenylsulfanyl) hexanamide (UPH-D-00204), methyl 5-phenylmethanesulfonylpentanoate (UPHD-206), N-[2-hydroxy-5-(trifluoromethyl) phenyl]-6-(phenylsulfanyl) hexanamide (UPHD-207), methyl 4-[methyl (phenyl) phosphoryl] butanoate (UPHD-208), N-[2-hydroxy-5-(trifluoromethyl) phenyl]-4-(phenylsulfanyl) butanamide (UPHD-209), N-(2-hydroxyphenyl)-6-[methyl (phenyl) phosphoryl] hexanamide (UPHD-210), N-(2-aminopyridin-3-yl)-4-(phenylsulfanyl) butanamide (UPHD-211), N-(4-hydroxypyridin-3-yl)-4-(phenylsulfanyl) butanamide (UPHD-212), N-(2-hydroxypyridin-3-yl)-4-(phenylsulfanyl) butanamide (UPHD-222), N-(3-hydroxypyridin-4-yl)-6-(phenylsulfanyl) hexanamide (UPHD-223), 2-({5-[(2-hydroxyphenyl) carbamoyl] pentyl} sulfanyl)-N-methylbenzamide (UPHD-224), methyl 4-(2-phenylethanesulfinyl) butanoate (UPHD-225), N-(3-aminopyridin-2-yl)-6-(phenylsulfanyl) hexanamide (UPHD-226), N-(3-aminopyridin-2-yl)-4-(phenylsulfanyl) butanamide (UPHD-227), or N-(3-aminopyridin-2-yl)-4-(phenylsulfanyl) butanamide (UPHD-228), or a pharmaceutically acceptable salt of any of the preceding.

6 . The method of claim 1 , wherein the insult leading to the sepsis is an infection.

7 . The method of claim 6 , wherein the infection is a hospital-acquired infection.

8 . The method of claim 6 , wherein the infection is a coronavirus infection.

9 . A method of reducing renal fibrosis in a patient having a sepsis-induced acute kidney injury, comprising administering to the patient, prior to development of irreversible fibrosis in the kidney, an amount of a selective histone deacetylase inhibitor effective to treat the sepsis-induced acute kidney injury and reduce fibrosis in the patient.

10 . The method of claim 9 , wherein the selective histone deacetylase inhibitor is 4-[(4-fluorophenyl) sulfanyl]-N-hydroxybutanamide (UPHD-29), N-hydroxy-4-[(4-methylphenyl) sulfanyl] butanamide (UPHD-28), 5-[(4-fluorophenyl) sulfanyl]-N-hydroxypentanamide (UPHD-34), 6-[(4-fluorophenyl) sulfanyl]-N-hydroxyhexanamide (UPHD-51), 4-{2 [(4-fluorophenyl) sulfanyl] ethyl}-N-hydroxybenzamide (UPHD-67), methyl 4-[(4-fluorophenyl) sulfanyl] butanoate (UPHD-30), methyl 4-[(4-methoxyphenyl) sulfanyl] butanoate (UPHD-22), methyl 6-(phenylsulfanyl) hexanoate (UPHD-47), methyl 6-[(4-fluorophenyl) sulfanyl] hexanoate (UPHD-48), N-(2-aminophenyl)-6-(phenylsulfanyl) hexanamide (UPHD-49), N-(2-aminophenyl)-6-[(4-fluorphenyl) sulfanyl] hexanamide (UPHD-53), 6-[(4-fluorophenyl) sulfanyl]-N-(2-hydroxyphenyl) hexanamide (UPHD-77), methyl 6-[4-(methylsulfanyl) phenoxy] hexanoate (UPHD-146), methyl 6-(4-methanesulfonylphenoxy) hexanoate (UPHD-149), methyl 4-({5-[(2-hydroxyphenyl) carbamoyl] pentyl} sulfanyl) benzoate (UPHD-150), methyl 4-({5-[(2-aminophenyl) carbamoyl] pentyl} sulfanyl) benzoate (UPHD-151), methyl 3-[(6-methoxy-6-oxohexyl) sulfanyl] benzoate (UPHD-152), methyl 2-[(6-methoxy-6-oxohexyl) sulfanyl] benzoate (UPHD-153), methyl 6-[(3-hydroxyphenyl) sulfanyl] hexanoate (UPHD-154), N-(2-hydroxyphenyl)-6-[4-(methylsulfanyl) phenoxy] hexanamide (UPHD-155), N-(2-aminophenyl)-6-[4-(methylsulfanyl) phenoxy] hexanamide (UPHD-156), methyl 6-[(2-hydroxyphenyl) sulfanyl] hexanoate (UPHD-158), methyl 2-({5-[(2-methyl 6-(4-hydroxyphenyl) carbamoyl] pentyl} sulfanyl) benzoate (UPHD-161), methanesulfinylphenoxy) hexanoate (UPHD-162), methy16-[(4-carbamoylphenyl) sulfanyl] hexanoate (UPHD-168), methyl 2-({5-[(2-aminophenyl) carbamoyl] pentyl} sulfanyl) benzoate (UPHD-170), methyl 6-{[4-(methylcarbamoyl) phenyl] sulfanyl} hexanoate (UPHD-171), 6-{[3-(methylcarbamoyl) phenyl] sulfanyl} hexanoate (UPHD-174), 4-({5-[(2-aminophenyl) carbamoyl] pentyl} sulfanyl)-N-methylbenzamide (UPHD-175), 4-({5-[(2-hydroxyphenyl) carbamoyl] pentyl} sulfanyl)-N-methylbenzamide (UPHD-176), methyl 5-(benzylsulfanyl) pentanoate (UPHD-178), methyl 4-[(2-phenylethyl) sulfanyl] butanoate (UPHD-179), methyl 5-{[(4-methoxyphenyl) methyl] sulfanyl} pentanoate (UPHD-180), 3-({5-[(2-hydroxyphenyl) carbamoyl] pentyl} sulfanyl)-N-methylbenzamide (UPHD-181), 3-({5-[(2-(UPHD-185), aminophenyl) carbamoyl] pentyl} sulfanyl)-N-methylbenzamide N-(2-aminophenyl)-5-(benzysulfanyl) pentanamide (UPHD-188), N-(2-aminophenyl)-5-{[(4-methoxyphenyl) methyl] sulfanyl} pentanamide phenylethyl) sulfanyl] butanamide (UPHD-190), 5-(benzylsulfanyl)-N-(2-N-(2-hydroxyphenyl)-5-{[(4-hydroxyphenyl) pentanamide (UPHD-191), (UPHD-189), N-(2-aminophenyl)-4-[(2-methoxyphenyl) methyl] sulfanyl} pentanamide (UPHD-192), N-(2-hydroxyphenyl)-4-[(2-phenylethyl) sulfanyl] butanamide (UPHD-193), N-hydroxy-5-{[(4-methoxyphenyl) methyl] sulfanyl} pentanamide (UPHD-194), 5-(benzylsulfanyl)-N-hydroxypentanamide (UPHD-195), N-hydroxy-4-[(2-phenylethyl) sulfanyl] butanamide (UPHD-196), methyl 6-(4-methanesulfonylbenzenesulfonyl) hexanoate (UPHD-197), N-(3-hydroxy-6-methylpyridin-2-yl)-4-(phenylsulfanyl) butanamide (UPHD-198), methyl 6-[methoxy (phenyl) phosphoryl] hexanoate (UPHD-199), methyl 5-phenylmethanesulfinylpentanoate (UPHD-201), methyl 6 {[2-(methylcarbamoyl) phenyl] sulfanyl} hexanoate (UPHD-202), methyl 4-[methoxy (phenyl) phosphoryl′butanoate (UPHD-203), N-(3-hydroxy-6-methylpyridin-2-yl)-6-(phenylsulfanyl) hexanamide (UPH-D-00204), methyl 5-phenylmethanesulfonylpentanoate (UPHD-206), N-[2-hydroxy-5-(trifluoromethyl)phenyl]-6-(phenylsulfanyl) hexanamide (UPHD-207), methyl 4-[methyl (phenyl)phosphoryl] butanoate (UPHD-208), N-[2-hydroxy-5-(trifluoromethyl)phenyl]-4-(phenylsulfanyl) butanamide (UPHD-209), N-(2-hydroxyphenyl)-6-[methyl (phenyl)phosphoryl] hexanamide (UPHD-210), N-(2-aminopyridin-3-yl)-4-(phenylsulfanyl) butanamide (UPHD-211), N-(4-hydroxypyridin-3-yl)-4-(phenylsulfanyl) butanamide (UPHD-212), N-(2-hydroxypyridin-3-yl)-4-(phenylsulfanyl) butanamide (UPHD-222), N-(3-hydroxypyridin-4-yl)-6-(phenylsulfanyl) hexanamide (UPHD-223), 2-({5-[(2-hydroxyphenyl) carbamoyl] pentyl} sulfanyl)-N-methylbenzamide (UPHD-224), methyl 4-(2-phenylethanesulfinyl) butanoate (UPHD-225), N-(3-aminopyridin-2-yl)-6-(phenylsulfanyl) hexanamide (UPHD-226), N-(3-aminopyridin-2-yl)-4-(phenylsulfanyl) butanamide (UPHD-227), or N-(3-aminopyridin-2-yl)-4-(phenylsulfanyl) butanamide (UPHD-228), or a pharmaceutically acceptable salt of any of the preceding.

11 . The method of claim 9 , wherein the selective histone deacetylase inhibitor is N-(2-hydroxyphenyl)-4-(phenylsulfanyl) butanamide (UPHD-186).

12 . The method of claim 9 , wherein the selective histone deacetylase inhibitor is methyl 4-(phenylsulfanyl) butanoate (UPHD-25).

13 . The method of claim 9 , wherein the sepsis is caused by an insult, and wherein the insult is an infection.

14 . The method of claim 13 , wherein the infection is a hospital-acquired infection.

15 . The method of claim 13 , wherein the infection is a coronavirus infection.

Assignments (2)
CONFIRMATORY LICENSE Recorded Jul 26, 2023
From: UNIVERSITY OF PITTSBURGH
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 064388/0577 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 31, 2023
From: KELLUM, JOHN A.; HUKRIEDE, NEIL; WEN, XIAOYAN
To: UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION
Reel/Frame 063810/0028 →
Continuity (3)
Provisional Application 62958424 · Jan 8, 2020
Provisional Application 62854654 · May 30, 2019
Related Publication 20220226266A1 · Jul 21, 2022
References Cited (33)
US 9670236B2 · Hukriede et al. · 2017 [cited by applicant]
US 10160705B2 · Day et al. · 2018 [cited by applicant]
US 10160715B2 · Swager et al. · 2018 [cited by applicant]
US 10233201B2 · Hukriede et al. · 2019 [cited by applicant]
US 20150246939A1 · Hukriede · 2015 [cited by examiner]
WO 2012109527A2 · 2012 [cited by applicant]
WO 2014071000A1 · 2014 [cited by applicant]
Skrypnyk et. al. (Am. J. Physiol. Renal Physiol., 310, F705-716) (Year: 2016). [cited by examiner]
Nolan et. al. (J. Am. Soc. Nephrol, 9(4), 710-718) (Year: 1998). [cited by examiner]
Zheng et. al. (J. Surg. Res., 192, 163-169) (Year: 2014). [cited by examiner]
Prasad et. al. (Indian J Nephrol. 30, 161-165, Epub May 13, 2020) (Year: 2020). [cited by examiner]
Tungsanga et. al. (Prevention of Chronic Kidney Disease and Its Complications in Older Adults, Drugs & Aging, 41:565-576) (Year: 2024). [cited by examiner]
Walther et. al. (Adv. Drug Deliv. Rev., 65-77) (Year: 2017). [cited by examiner]
Skyrpynyk et. al. (Am. J. Physiol. Renal Physiol, 310, F705-F716 (Year: 2016). [cited by examiner]
Brewster et al., “Cyclodextrins as pharmaceutical solubilizers”, 2007, Adv Drug Deliv. Rev., vol. 59, pp. 645-666. [cited by applicant]
Brilli et al., “HDAC inhibitors in kidney development and disease”, 2013, Pediatr Nephrol., vol. 28(10), pp. 1909-1921. [cited by applicant]
Cavanaugh et al., “Urine Sediment Examination in the Diagnosis and Management of Kidney Disease: Core Curriculum 2019”, 2019, Am J Kidney Dis., vol. 73(2), pp. 258-272. [cited by applicant]
Devy et al., “Selective Inhibition of Matrix Metalloproteinase-14 Blocks Tumor Growth, Invasion, and Angiogenesis”, 2009, Cancer Res., vol. 69(4), pp. 1517-1526. [cited by applicant]
Haines et al., “Acute Kidney Injury in Trauma Patients Admitted to Critical Care: Development and Validation of a Diagnostic Prediction Model”, 2018, Sci Rep., vol. 8:3665, pp. 1-9. [cited by applicant]
Higashi et al., “Molecular design of a highly selective and strong protein inhibitor against matrix metalloproteinase-2 (MMP-2)”, 2013, J Biol Chem., vol. 288(13), pp. 9066-9076. [cited by applicant]
Kaneko et al., “Selective Inhibition of Membrane Type 1 Matrix Metalloproteinase Abrogates Progression of Experimental Inflammatory Arthritis: Synergy With Tumor Necrosis Factor Blockade”, 2016, Arthritis Rheumatol., vo… [cited by applicant]
Kellum et al., “Sepsis-Associated Acute Kidney Injury: A Problem Deserving of New Solutions”, 2019, Nephron, vol. 143(3), pp. 174-178. [cited by applicant]
Loftsson et al., “Self-Association of Cyclodextrins and Cyclodextrin Complexes”, 2004, J Pharm Sci., vol. 93(5), pp. 1091-1099. [cited by applicant]
Loftsson et al., “Cyclodextrins in drug delivery”, 2005, Expert Opin Drug Deliv., vol. 2(2), pp. 335-351. [cited by applicant]
Mehta et al., “Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury”, 2007, Critical Care, vol. 11(2). [cited by applicant]
Rasheed et al., “Cyclodextrins as Drug Carrier Molecule: A Review”, 2008, Sci Pharm., vol. 76, pp. 567-598. [cited by applicant]
Reichsoellner et al., “Clinical evaluation of multiple inflammation biomarkers for diagnosis and prognosis for patients with systemic inflammatory response syndrome”, 2014, J Clin Microbiol., vol. 52(11), pp. 4063-4066. [cited by applicant]
“Remington: The Science and Practice of Pharmacy”, 2005, Lippincott Williams & Wilkins, 21st edition, Chapters. 37, 39, 40, 41, 42, and 45. [cited by applicant]
Sela-Passwell et al., “Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential”, 2012, Nature Medicine, vol. 18(1), pp. 143-147. [cited by applicant]
Thurman et al., “Recent advances in renal imaging”, 2018, F1000Research, vol. 29(7), pp. 1-13. [cited by applicant]
Xu et al., “Inhibition of MMP-2 gelatinolysis by targeting exodomain-substrate interactions”, 2007, Biochem J., vol. 406 (1), pp. 147-155. [cited by applicant]
Rittirsch et al., “Immunodesign of experimental sepsis by cecal ligation and puncture”, Nat Protoc., 2009, pp. 31-36, vol. 4. [cited by applicant]
Hyslop et al., “Methods for sample preparation for direct immunoassay measurement of analytes in tissue homogenates: ELISA assay of amyloid beta-peptides”, Current Protocols in Neuroscience, 2002, John Wiley & Sons, Inc… [cited by applicant]