A System for Discovering Novel Uricosurics Targeting Urate Transporter 1 Based on In Vitro and In Vivo Modeling

Area of Science:

• Pharmacology
• Nephrology
• Biochemistry

Background:

• Hyperuricemia is a growing global health concern linked to metabolic and cardiovascular diseases.
• Uricosurics promote uric acid excretion but potent and safe options are needed.
• Targeting renal urate transporter 1 (URAT1) is crucial for managing uric acid homeostasis.

Purpose of the Study:

• To establish novel in vitro and in vivo models for discovering uricosuric compounds.
• To identify potent inhibitors of URAT1, the primary kidney urate transporter.
• To evaluate the therapeutic potential of identified compounds in hyperuricemic models.

Main Methods:

• Established a cell-based assay using HEK293 cells expressing human URAT1 (hURAT1) for in vitro screening.
• Developed subacute (sub-HUA) and chronic (Ch-HUA) hyperuricemic mouse models for in vivo evaluation.
• Assessed compound CC18002 for URAT1 inhibition, uric acid-lowering effects, and impact on xanthine oxidoreductase activity.

Main Results:

• Compound CC18002 demonstrated potent URAT1 inhibition with an IC50 of 1.69 μM.
• CC18002 significantly reduced uric acid levels in both sub-HUA and Ch-HUA mice, comparable to benzbromarone.
• CC18002 did not affect xanthine oxidoreductase activity, indicating a specific uricosuric mechanism.

Conclusions:

• A novel screening system comprising cell and mouse models for uricosuric discovery was successfully developed.
• Compound CC18002 emerged as a promising URAT1 inhibitor candidate for treating hyperuricemia.
• The developed models provide a valuable platform for identifying future uricosuric therapeutics.