Small Molecule Drugs for Acute Kidney Injury and Fibrosis

University of Pittsburgh researchers have developed a new class of small molecule drugs based on sulfonamide compounds that treat acute kidney injury (AKI) and fibrosis by enhancing renal recovery and reducing fibrotic scarring.

Description

AKI is associated with 5–15% of hospitalizations, and up to 60% of critical care admissions. AKI in-hospital mortality can reach 30–50% and 12–15% of survivors may require permanent dialysis. There are no approved therapies that accelerate recovery or prevent subsequent fibrosis. Chronic kidney disease affects 10–14% of the global population and fibrosis is a hallmark of disease progression. Sulfonamide compounds are small molecule analogs, derived from PTBA (4-phenoxy-N-phenylbutanamide) but without the need for a pro-drug conversion which many current drug candidates require, and researchers have designed these to improve survival and reduce injury-related markers across multiple research models. Studies have shown that the lead compounds UPHH-207 and UPHH-231 significantly improve zebrafish survival, lower injury and inflammation markers in human kidney organoids, and enhance kidney function in mice. This invention aims to address the high mortality and limited treatment options in AKI and related fibrosis associated disease.

Applications

• Acute kidney injury (AKI).
• Organ fibrosis.
• Chronic kidney disease/renal fibrosis.

Advantages

The lead sulfonamide compounds deliver multiple benefits across disease models. Zebrafish exposed to induced kidney injury showed improved survival when treated with compounds 207 and 231; the experimental results indicate a lower risk of death compared with controls making them clear priorities for further development. In newly developed human models, UPHH‑207 markedly lowered key injury biomarkers and well established inflammatory/fibrotic markers, while also reducing collagen deposition. Pharmacokinetic data revealed that UPHH‑207 reaches peak plasma levels within 5 minutes and has a half‑life of over 30 minutes, supporting convenient dosing. Daily treatment improved kidney function markers and significantly reduced renal fibrosis in a mouse l AKI model.

Invention Readiness

The lead compounds have been synthesized and tested in vitro and in vivo with validated mechanisms of action and efficacy demonstrated in zebrafish, human kidney organoids and rodent models, and are stable small molecules that do not require pro drug conversion.

IP Status

https://patents.google.com/patent/WO2024215882A2

Related Publication(s)

Long, K. et al (2022) Validation of HDAC8 Inhibitors as Drug Discovery Starting Points to Treat Acute Kidney Injury. ACS Pharmacol Transl Sci, 16;5(4):207-215 https://pubmed.ncbi.nlm.nih.gov/35434532/

Skrypnyk, N et al (2015) Delay treatment with PTBA analogs reduces postinjury renal fibrosis after kidney injury. Am J Physiol Renal Physiol, 9;310(8):F705–F716. https://pmc.ncbi.nlm.nih.gov/articles/PMC4835925/ 

Eeshrita Jog, BS et al (2025) Nontraditional Models for Acute Kidney Injury Research: Organoids, Zebrafish, and more. Semin Nephrol 45;6,151668. https://pubmed.ncbi.nlm.nih.gov/40957762/