Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters.

Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters. Am J Physiol Renal Physiol. 2014 Oct 8; Authors: Ren H, Wang Y, Xing Y, Ran J, Liu M, Lei T, Zhou H, Li R, Sands JM, Yang B Abstract Urea transporters (UT) play an important role in the urine concentration mechanism by mediating intrarenal urea recycling, suggesting that UT inhibitors could have therapeutic use as a novel class of diuretic. Recently we found a thienoquinolin UT inhibitor, PU-14, which exhibited diuretic activity. The purpose of this study was to identify more potent UT inhibitors that strongly inhibit UT-A isoforms in the inner medullary collecting duct (IMCD). Efficient thienoquinolin UT inhibitors were identified by structure-activity relationship analysis. Urea transport inhibition activity was assayed in perfused rat terminal IMCDs. Diuretic activity of the compound was determined in rats and mice using metabolic cages. The results show that the compound PU-48 exhibited potent UT-A inhibition activity. The inhibition rate was 69.5% with an IC50 of 0.32 μM. PU-48 significantly inhibited urea transport in perfused rat terminal IMCDs. PU-48 caused significant diuresis in UT-B null mice, which indicates that UT-A is the target of PU-48. The diuresis caused by PU-48 did not change blood Na(+), K(+), or Cl- levels, or non-urea solute excretion in rats and mice. No toxicity was detected in cells or animals treated with PU-48. The results indicate that thienoqui...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research

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