ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2014
Diuresis and reduced urinary osmolality in rats produced by small-molecule UT-A-selective urea transport inhibitors.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 23 citations in OpenAlex.
- Comparison of the effects of tolvaptan and furosemide on renal water and sodium excretion in patients with heart failure and advanced chronic kidney disease: a subanalysis of the K-STAR study.Clinical and experimental nephrology · 2018Trial
- Epithelial plasma membrane transporters as drug targets.Physiological reviews · 2026Review
- Small-Molecule Inhibitors and Drug Discovery of Urea Transporters.Sub-cellular biochemistry · 2025Review
- Protein Structures of Urea Transporters.Sub-cellular biochemistry · 2025Review
- Structural insights into the mechanisms of urea permeation and distinct inhibition modes of urea transporters.Nature communications · 2024Article
- A critical analysis of urea transporter B inhibitors: molecular fingerprints, pharmacophore features for the development of next-generation diuretics.Molecular diversity · 2022Article
- Inhibition of urea transporter ameliorates uremic cardiomyopathy in chronic kidney disease.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1.Journal of medicinal chemistry · 2018Article
- Emerging Targets of Diuretic Therapy.Clinical pharmacology and therapeutics · 2017Review
- Urea transport and clinical potential of urearetics.Current opinion in nephrology and hypertension · 2016Review
- Phenylphthalazines as small-molecule inhibitors of urea transporter UT-B and their binding model.Acta pharmacologica Sinica · 2016Article
- Imaging Renal Urea Handling in Rats at Millimeter Resolution using Hyperpolarized Magnetic Resonance Relaxometry.Tomography (Ann Arbor, Mich.) · 2016Article
- Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2016Article
- CFTR activator increases intestinal fluid secretion and normalizes stool output in a mouse model of constipation.Cellular and molecular gastroenterology and hepatology · 2016Article
- Structure-activity analysis of thiourea analogs as inhibitors of UT-A and UT-B urea transporters.Biochimica et biophysica acta · 2015Article
- Urea transporter proteins as targets for small-molecule diuretics.Nature reviews. Nephrology · 2015Review
- Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
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, γ-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 ∼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 γ-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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.