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Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 FASEB+J 2014 ; 28 (9): 3878-90 Nephropedia Template TP
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Diuresis and reduced urinary osmolality in rats produced by small-molecule UT-A-selective urea transport inhibitors #MMPMID24843071
Esteva-Font C; Cil O; Phuan PW; Su T; Lee S; Anderson MO; Verkman AS
FASEB J 2014[Sep]; 28 (9): 3878-90 PMID24843071show ga
Urea transport (UT) proteins of the UT-A class are expressed in epithelial cells in kidney tubules, where they are required for the formation of a concentrated urine by countercurrent multiplication. Here, using a recently developed high-throughput assay to identify UT-A inhibitors, a screen of 50,000 synthetic small molecules identified UT-A inhibitors of aryl-thiazole, gamma-sultambenzosulfonamide, aminocarbonitrile butene, and 4-isoxazolamide chemical classes. Structure-activity analysis identified compounds that inhibited UT-A selectively by a noncompetitive mechanism with IC50 down to approximately 1 muM. Molecular modeling identified putative inhibitor binding sites on rat UT-A. To test compound efficacy in rats, formulations and administration procedures were established to give therapeutic inhibitor concentrations in blood and urine. We found that intravenous administration of an indole thiazole or a gamma-sultambenzosulfonamide at 20 mg/kg increased urine output by 3-5-fold and reduced urine osmolality by approximately 2-fold compared to vehicle control rats, even under conditions of maximum antidiuresis produced by 1-deamino-8-D-arginine vasopressin (DDAVP). The diuresis was reversible and showed urea > salt excretion. The results provide proof of concept for the diuretic action of UT-A-selective inhibitors. UT-A inhibitors are first in their class salt-sparing diuretics with potential clinical indications in volume-overload edemas and high-vasopressin-associated hyponatremias.
|Animals[MESH]
|Biological Transport/*drug effects[MESH]
|Chromatography, Liquid[MESH]
|Diuresis/*drug effects/physiology[MESH]
|Dogs[MESH]
|High-Throughput Screening Assays[MESH]
|Kidney Concentrating Ability/*drug effects[MESH]
|Madin Darby Canine Kidney Cells[MESH]
|Male[MESH]
|Membrane Transport Proteins/*chemistry/metabolism[MESH]
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FASEB+J 2014 ; 28 (9): 3878-90
