Publication Date:
2014-09-03
Description:
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, -sultambenzosulfonamide, aminocarbonitrile butene, and 4-isoxazolamide chemical classes. Structure-activity analysis identified compounds that inhibited UT-A selectively by a noncompetitive mechanism with IC 50 down to ~1 μM. 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 -sultambenzosulfonamide at 20 mg/kg increased urine output by 3–5-fold and reduced urine osmolality by ~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.—Esteva-Font, C., Cil, O., Phuan, P.-W., Su, T., Lee, S., Anderson, M. O., Verkman, A. S. Diuresis and reduced urinary osmolality in rats produced by small-molecule UT-A-selective urea transport inhibitors.
Print ISSN:
0892-6638
Electronic ISSN:
1530-6860
Topics:
Biology
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