Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1

Lee, Sujin; Çil, Onur; Diez‐Cecilia, Elena; Anderson, Marc O.

doi:10.1021/acs.jmedchem.8b00343

Cited by 20 publications

(16 citation statements)

References 36 publications

(63 reference statements)

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“…However, mice showed mild increased urine output and decreased urine osmolality in high vasopressin and fluid-retaining conditions after intraperitoneal administration 26 . Verkman's group 33 reported 1,2,4-triazoloquinoxaline ( Fig. 1 B) as an UT-A1 inhibitor, which significantly increased the urine output and reduced the urine osmolality after intravenous administration in a rat model.…”

Section: Introductionmentioning

confidence: 90%

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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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Section: Introductionmentioning

confidence: 90%

“…In recent decades, several classes of potent small molecule inhibitors of UTs have been identified 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 . Among these inhibitors, the triazolothienopyrimidine inhibitor UTB inh -14 ( 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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“…Small-molecule screening has identified potent and selective inhibitors for various UTs. Additionally, emerging evidence from experiments suggests that UT inhibitors can be developed as a novel class of diuretic drugs (Esteva-Font et al 2015;Yao et al 2012;Zhao et al 2019;Lee et al 2018;Li et al 2014;Li et al 2019). Understanding the mechanism of binding and permeation of urea and urea analogues across UTs might be useful structural determinants which may aid in optimizing the binding of clinically useful UT inhibitors.…”

Section: Amide-aromatic Stacking Interactionsmentioning

confidence: 99%

Urea-aromatic interactions in biology

Raghunathan

Jaganade

2020

Biophys Rev

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Noncovalent interactions are key determinants in both chemical and biological processes. Among such processes, the hydrophobic interactions play an eminent role in folding of proteins, nucleic acids, formation of membranes, protein-ligand recognition, etc.. Though this interaction is mediated through the aqueous solvent, the stability of the above biomolecules can be highly sensitive to any small external perturbations, such as temperature, pressure, pH, or even cosolvent additives, like, urea-a highly soluble small organic molecule utilized by various living organisms to regulate osmotic pressure. A plethora of detailed studies exist covering both experimental and theoretical regimes, to understand how urea modulates the stability of biological macromolecules. While experimentalists have been primarily focusing on the thermodynamic and kinetic aspects, theoretical modeling predominantly involves mechanistic information at the molecular level, calculating atomistic details applying the force field approach to the high level electronic details using the quantum mechanical methods. The review focuses mainly on examples with biological relevance, such as (1) urea-assisted protein unfolding, (2) ureaassisted RNA unfolding, (3) urea lesion interaction within damaged DNA, (4) urea conduction through membrane proteins, and (5) protein-ligand interactions those explicitly address the vitality of hydrophobic interactions involving exclusively the urea-aromatic moiety.

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“…The spectroscopic data were in agreement with those in the literature. 32 5-Chloro-3-(4-(difluoromethoxy)phenyl)- [1,2,4]triazolo [4,3-a]pyrazine (16).…”

Section: 29mentioning

confidence: 99%

“…Compound 11 has been reported to have nanomolar potency as an inhibitor of the kidney urea transporter UT-A1. 16 Compound 12 was recently patented in 2016 as a renal outer medullary potassium channel (ROMK) inhibitor. 17 Sitagliptin (13) was approved by the FDA in 2006 as an antidiabetic drug (dipeptidyl peptidase (DPP)-IV inhibitor).…”

Section: Introductionmentioning

confidence: 99%

Tele-Substitution Reactions in the Synthesis of a Promising Class of Antimalarials

Korsik

Tse²,

Smith³

et al. 2020

Preprint

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We have discovered and studied a telesubstitution reaction in a biologically important heterocyclic ring system. Conditions that favour the tele-substitution pathway were identified: the use of increased equivalents of the nucleophile or decreased equivalents of base, or the use of softer nucleophiles, less polar solvents and larger halogens on the electrophile. Using results from X-ray crystallography and isotope labelling experiments a mechanism for this unusual transformation is proposed. We focused on this triazolopyrazine as it is the core structure of the in vivo active anti-plasmodium compounds of Series 4 of the Open Source Malaria consortium. Archive of the electronic laboratory notebook with the description of all conducted experiments and raw NMR data could be accessed via following link <a href="https://ses.library.usyd.edu.au/handle/2123/21890">https://ses.library.usyd.edu.au/handle/2123/21890</a> . For navigation between entries of laboratory notebook please use file "Strings for compounds in the article.pdf" that works as a reference between article codes and notebook codes, also this file contain SMILES for these compounds.

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Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1

Cited by 20 publications

References 36 publications

Discovery of novel diarylamides as orally active diuretics targeting urea transporters

Discovery of novel diarylamides as orally active diuretics targeting urea transporters

Urea-aromatic interactions in biology

Tele-Substitution Reactions in the Synthesis of a Promising Class of Antimalarials

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