Triazolothienopyrimidine Inhibitors of Urea Transporter UT-B Reduce Urine Concentration

Yao, Chenjuan; Anderson, Marc O.; Zhang, Jicheng; Yang, Baoxue; Phuan, Puay‐Wah; Verkman, A. S.

doi:10.1681/asn.2011070751

Cited by 47 publications

(66 citation statements)

References 41 publications

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“…In a follow-on study, 100,000 compounds were screened using mouse erythrocytes with the goal of identifying potent inhibitors of rodent (and human) UT-B [34]. The screen produced triazolothienopyrimidine UT-B inhibitors, with the most potent compound being 3-(4-ethyl-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-thiophen-2-ylmethylamine (UTB inh -14, Fig.…”

Section: Ut-b Inhibitorsmentioning

confidence: 99%

“…To study in vivo effects of UTB inh -14 on urinary concentrating function, compound administration dose, route, and timing were established, from liquid chromatography/mass spectrometry assays, to maintain predicted therapeutic compound concentrations in blood, kidney, and urine [34]. Following intraperitoneal administration of UTB inh -14 in mice to achieve therapeutic concentrations in kidney, urine osmolality following dDAVP in UTB inh -14-treated mice was ~700 mosm/kg H 2 O lower than in vehicle-treated mice (Fig.…”

Section: Ut-b Inhibitorsmentioning

confidence: 99%

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Small-Molecule Inhibitors of Urea Transporters

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Anderson

et al. 2014

Subcellular Biochemistry

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Urea transporter (UT) proteins, which include isoforms of UT-A in kidney tubule epithelia and UT-B in vasa recta endothelia and erythrocytes, facilitate urinary concentrating function. Inhibitors of urea transporter function have potential clinical applications as sodium-sparing diuretics, or ‘urearetics,’ in edema from different etiologies, such as congestive heart failure and cirrhosis, as well as in syndrome of inappropriate antidiuretic hormone (SIADH). High-throughput screening of drug-like small molecules has identified UT-A and UT-B inhibitors with nanomolar potency. Inhibitors have been identified with different UT-A versus UT-B selectivity profiles and putative binding sites on UT proteins. Studies in rodent models support the utility of UT inhibitors in reducing urinary concentration, though testing in clinically relevant animal models of edema has not yet been done.

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Section: Ut-b Inhibitorsmentioning

confidence: 99%

Section: Ut-b Inhibitorsmentioning

confidence: 99%

Small-Molecule Inhibitors of Urea Transporters

Esteva‐Font

Çil

Anderson

et al. 2014

Subcellular Biochemistry

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“…Additionally, administration of UTB(inh)-14 blunts DDAVP-stimulated increases in urine osmolality (159). The diuretic effect of UTB (inh)-14 is not observed in UT-B knockout mice, suggesting that effects of UTB(inh)-14 on urine concentration are specific to UT-B (159). These data illustrate that urea transport inhibitors represent a novel class of diuretics that have a different mechanism of action from conventional diuretics or aquaretics.…”

Section: Urea Transportersmentioning

confidence: 88%

“…Intraperitoneal administration of UTB(inh)-14 in mice with free access to water increases urine output and decreases urine osmolality. Additionally, administration of UTB(inh)-14 blunts DDAVP-stimulated increases in urine osmolality (159). The diuretic effect of UTB (inh)-14 is not observed in UT-B knockout mice, suggesting that effects of UTB(inh)-14 on urine concentration are specific to UT-B (159).…”

Section: Urea Transportersmentioning

confidence: 98%

Novel diuretic targets

Denton

Pao

Maduke

2013

American Journal of Physiology-Renal Physiology

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As the molecular revolution continues to inform a deeper understanding of disease mechanisms and pathways, there exist unprecedented opportunities for translating discoveries at the bench into novel therapies for improving human health. Despite the availability of several different classes of antihypertensive medications, only about half of the 67 million Americans with hypertension manage their blood pressure appropriately. A broader selection of structurally diverse antihypertensive drugs acting through different mechanisms would provide clinicians with greater flexibility in developing effective treatment regimens for an increasingly diverse and aging patient population. An emerging body of physiological, genetic, and pharmacological evidence has implicated several renal ion-transport proteins, or regulators thereof, as novel, yet clinically unexploited, diuretic targets. These include the renal outer medullary potassium channel, ROMK (Kir1.1), Kir4.1/5.1 potassium channels, ClC-Ka/b chloride channels, UTA/B urea transporters, the chloride/bicarbonate exchanger pendrin, and the STE20/SPS1-related proline/alanine-rich kinase (SPAK). The molecular pharmacology of these putative targets is poorly developed or lacking altogether; however, recent efforts by a few academic and pharmaceutical laboratories have begun to lessen this critical barrier. Here, we review the evidence in support of the aforementioned proteins as novel diuretic targets and highlight examples where progress toward developing small-molecule pharmacology has been made.

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“…104 The most potent UT-B inhibitor identified in this screening was the triazolothienopyrimidine 3-(4-ethyl-benzenesulphonyl)-thieno[2,3-e][1,2,3] triazolo[1,5-a]pyrimidin-5-yl]-thiophen-2-ylmethylamine (UTB inh -14; Figure 5). UTB inh -14, which was synthesized and purified in five steps, fully and reversibly inhibited urea transport with an IC 50 of 10 nM for human UT-B (Figure 5b) and 25 nM for mouse UT-B.…”

Section: Ut Inhibitorsmentioning

confidence: 99%

Urea transporter proteins as targets for small-molecule diuretics

Esteva‐Font

Anderson

2014

Nat Rev Nephrol

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Conventional diuretics such as furosemide and thiazides target salt transporters in kidney tubules, but urea transporters (UTs) have emerged as alternative targets. UTs are a family of transmembrane channels expressed in a variety of mammalian tissues, in particular the kidney. UT knockout mice and humans with UT mutations exhibit reduced maximal urinary osmolality, demonstrating that UTs are necessary for the concentration of urine. Small-molecule screening has identified potent and selective inhibitors of UT-A, the UT protein expressed in renal tubule epithelial cells, and UT-B, the UT protein expressed in vasa recta endothelial cells. Data from UT knockout mice and from rodents administered UT inhibitors support the diuretic action of UT inhibition. The kidney-specific expression of UT-A1, together with high selectivity of the small-molecule inhibitors, means that off-target effects of such small-molecule drugs should be minimal. This Review summarizes the structure, expression and function of UTs, and looks at the evidence supporting the validity of UTs as targets for the development of salt-sparing diuretics with a unique mechanism of action. UT-targeted inhibitors may be useful alone or in combination with conventional diuretics for therapy of various oedemas and hyponatraemias, potentially including those refractory to treatment with current diuretics.

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Triazolothienopyrimidine Inhibitors of Urea Transporter UT-B Reduce Urine Concentration

Cited by 47 publications

References 41 publications

Small-Molecule Inhibitors of Urea Transporters

Small-Molecule Inhibitors of Urea Transporters

Novel diuretic targets

Urea transporter proteins as targets for small-molecule diuretics

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