ArticleActa pharmacologica Sinica2016
Phenylphthalazines as small-molecule inhibitors of urea transporter UT-B and their binding model.
Article in Acta pharmacologica Sinica, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 14 citations in OpenAlex.
- Identification and Validation of Urea Transporter B Inhibitor fromMolecules (Basel, Switzerland) · 2025Article
- Small-Molecule Inhibitors and Drug Discovery of Urea Transporters.Sub-cellular biochemistry · 2025Review
- Article
- A critical analysis of urea transporter B inhibitors: molecular fingerprints, pharmacophore features for the development of next-generation diuretics.Molecular diversity · 2022Article
- Preclinical Pharmacokinetic Studies of a Novel Diuretic Inhibiting Urea Transporters.Molecules (Basel, Switzerland) · 2022Article
- Discovery of novel diarylamides as orally active diuretics targeting urea transporters.Acta pharmaceutica Sinica. B · 2021Article
- The urea transporter UT-A1 plays a predominant role in a urea-dependent urine-concentrating mechanism.The Journal of biological chemistry · 2020Article
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimUrea transporters (UT) are a family of transmembrane proteins that specifically transport urea. UT inhibitors exert diuretic activity without affecting electrolyte balance. The purpose of this study was to discover novel UT inhibitors and determine the inhibition mechanism.
methodsThe primary screening urea transporter B (UT-B) inhibitory activity was conducted in a collection of 10 000 diverse small molecules using mouse erythrocyte lysis assay. After discovering a hit with a core structure of 1-phenylamino-4-phenylphthalazin, the UT-B inhibitory activity of 160 analogs were examined with a stopped-flow light scattering assay and their structure-activity relationship (SAR) was analyzed. The inhibition mechanism was further investigated using in silico assays.
resultsA phenylphthalazine compound PU1424, chemically named 5-(4-((4-methoxyphenyl) amino) phthalazin-1-yl)-2-methylbenzene sulfonamide, showed potent UT-B inhibition activity, inhibited human and mouse UT-B-mediated urea transport with IC50 value of 0.02 and 0.69 μmol/L, respectively, and exerted 100% UT-B inhibition at higher concentrations. The compound PU1424 did not affect membrane urea transport in mouse erythrocytes lacking UT-B. Structure-activity analysis revealed that the analogs with methoxyl group at R4 and sulfonic amide at R2 position exhibited the highest potency inhibition activity on UT-B. Furthermore, in silico assays validated that the R4 and R2 positions of the analogs bound to the UT-B binding pocket and exerted inhibition activity on UT-B.
conclusionThe compound PU1424 is a novel inhibitor of both human and mouse UT-B with IC50 at submicromolar ranges. Its binding site is located at the So site of the UT-B structure.
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