Pharmacokinetics, Tissue Distribution and Excretion of a Novel Diuretic (PU-48) in Rats

Zhang, Zhiyuan; Zhang, Hua; Liú, Dan; Lu, Yingyuan; Wang, Xin; Li, Pu; Lou, Ya-Qing; Yang, Baoxue; Lou, Yonggen; Lu, Chuang; Zhang, Qiang; Zhang, Guoliang

doi:10.3390/pharmaceutics10030124

Cited by 8 publications

(4 citation statements)

References 53 publications

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“…Actually, there have been certain UT inhibitors (e.g. PU-14, PU-48, PU1424, CB-20, and 8n) discovered and developed to inhibit all UTs (42)(43)(44)(45)(46)(47). In this case, however, side effects can not be ignored because that UT-B-KO mouse was found to exhibit depression-like behavior (48) and to induce DNA damage and apoptosis in bladder (49), which attributed to elevated level of urea.…”

Section: Discussionmentioning

confidence: 99%

The urea transporter UT-A1 plays a predominant role in a urea-dependent urine-concentrating mechanism

Geng

Zhang

et al. 2020

Journal of Biological Chemistry

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Urea transporters are a family of urea-selective channel proteins expressed in multiple tissues that play an important role in the urine-concentrating mechanism of the mammalian kidney. Previous studies have shown that knockout of urea transporter (UT)-B, UT-A1/A3, or all UTs leads to urea-selective diuresis, indicating that urea transporters have important roles in urine concentration. Here, we sought to determine the role of UT-A1 in the urine-concentrating mechanism in a newly developed UT-A1–knockout mouse model. Phenotypically, daily urine output in UT-A1–knockout mice was nearly 3-fold that of WT mice and 82% of all-UT–knockout mice, and the UT-A1–knockout mice had significantly lower urine osmolality than WT mice. After 24-h water restriction, acute urea loading, or high-protein (40%) intake, UT-A1–knockout mice were unable to increase urine-concentrating ability. Compared with all-UT–knockout mice, the UT-A1–knockout mice exhibited similarly elevated daily urine output and decreased urine osmolality, indicating impaired urea-selective urine concentration. Our experimental findings reveal that UT-A1 has a predominant role in urea-dependent urine-concentrating mechanisms, suggesting that UT-A1 represents a promising diuretic target.

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Section: Discussionmentioning

confidence: 99%

The urea transporter UT-A1 plays a predominant role in a urea-dependent urine-concentrating mechanism

Geng

Zhang

et al. 2020

Journal of Biological Chemistry

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“…Further optimization of PU-48 yielded a thienopyridine UT inhibitor ( Fig. 1 D) with improved water solubility and activity almost equal to that of PU-48 in vitro and in vivo 32 , 37 , 39 , 40 . Dimethylthiourea, an urea analogue with millimolar potency for UT inhibition was identified in previous studies ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Discovery of novel diarylamides as orally active diuretics targeting urea transporters

Zhang

Zhao

Wang

et al. 2021

Acta Pharmaceutica Sinica B

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Urea transporters (UT) play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing diuretics. Thus, UT inhibitors are promising for development as novel diuretics. In the present study, a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput screening. Optimization of the inhibitor led to the identification of a promising preclinical candidate, N -[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide ( 1H ), with excellent in vitro UT inhibitory activity at the submicromolar level . The half maximal inhibitory concentrations of 1H against UT-B in mouse, rat, and human erythrocyte were 1.60, 0.64, and 0.13 μmol/L, respectively. Further investigation suggested that 8 μmol/L 1H more powerfully inhibited UT-A1 at a rate of 86.8% than UT-B at a rate of 73.9% in MDCK cell models. Most interestingly, we found for the first time that oral administration of 1H at a dose of 100 mg/kg showed superior diuretic effect in vivo without causing electrolyte imbalance in rats. Additionally, 1H did not exhibit apparent toxicity in vivo and in vitro , and possessed favorable pharmacokinetic characteristics. 1H shows promise as a novel diuretic to treat hyponatremia accompanied with volume expansion and may cause few side effects.

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“…The authors also reported reduced blood pressure and essentially no physiological abnormalities in the extrarenal organs. Indeed, this specific disorder in the ability of the kidney to concentrate urine in UTs knockout mice supports the rationale behind the development of UT inhibitors as novel diuretics (Esteva-Font et al, 2013;Zhang et al, 2018).…”

Section: Introductionmentioning

confidence: 66%

Water transport mediated by murine Urea Transporters: Implications for urine concentration mechanisms

2020

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Urea transporters (UTs) facilitate urea diffusion across cell membranes and play an important role in the urinary concentration mechanisms in the kidney. Herein, we injected cRNAs encoding for c-Myc-tagged murine UT-B, UT-A2 or UT-A3 (versus water-injected control) in Lithobates oocytes and evaluated oocyte surface protein expression with biotinylation and immunoblotting, urea uptake using [14C] counts and water permeability (Pf) by video microscopy. Immunoblots of UT-injected oocyte membranes revealed bands with a molecular weight consistent with that of a UT monomer (34 kDa), and UT-injected oocytes displayed significantly increased and phloretin-sensitive urea uptake and Pf when compared to day-matched control oocytes. Subtracting the water-injected urea uptake or Pf values from those of UT-injected oocytes yielded UT-dependent values*. We demonstrate for the first time that UT-A2 and UT-A3 can transport water, and we confirm that UT-B is permeable to water. Moreover, the [14C] urea*/Pf* ratios fell in the sequence mUT-B>mUT-A2>mUT-A3, indicating that UTs can exhibit selectivity to urea and/or water. It is likely that specific kidney regions with high levels of UTs will exhibit increased urea and/or water permeabilities, directly influencing urine concentration. Furthermore, UT-mediated water transport activity must be considered when developing UT-inhibitors as novel diuretics.This article has an associated First Person interview with the first author of the paper.

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Pharmacokinetics, Tissue Distribution and Excretion of a Novel Diuretic (PU-48) in Rats

Cited by 8 publications

References 53 publications

The urea transporter UT-A1 plays a predominant role in a urea-dependent urine-concentrating mechanism

The urea transporter UT-A1 plays a predominant role in a urea-dependent urine-concentrating mechanism

Discovery of novel diarylamides as orally active diuretics targeting urea transporters

Water transport mediated by murine Urea Transporters: Implications for urine concentration mechanisms

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