title: Structure-activity analysis of thiourea analogs as inhibitors of UT-A and UT-B urea transporters.
abstract: Small-molecule inhibitors of urea transporter (UT) proteins in kidney have potential application as novel salt-sparing diuretics. The urea analog dimethylthiourea (DMTU) was recently found to inhibit the UT isoforms UT-A1 (expressed in kidney tubule epithelium) and UT-B (expressed in kidney vasa recta endothelium) with IC50 of 2-3 mM, and was shown to have diuretic action when administered to rats. Here, we measured UT-A1 and UT-B inhibition activity of 36 thiourea analogs, with the goal of identifying more potent and isoform-selective inhibitors, and establishing structure-activity relationships. The analog set systematically explored modifications of substituents on the thiourea including alkyl, heterocycles and phenyl rings, with different steric and electronic features. The analogs had a wide range of inhibition activities and selectivities. The most potent inhibitor, 3-nitrophenyl-thiourea, had an IC50 of ~0.2 mM for inhibition of both UT-A1 and UT-B. Some analogs such as 4-nitrophenyl-thiourea were relatively UT-A1 selective (IC50 1.3 vs. 10 mM), and others such as thioisonicotinamide were UT-B selective (IC50>15 vs. 2.8 mM).
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, CA 94143-0521, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Esteva-Font
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, CA 94143-0521, USA.
authors.forename: Puay-Wah
authors.initials: PW
authors.lastname: Phuan
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, CA 94143-0521, USA.
authors.forename: Sujin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, CA 94143-0521, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132-4136, USA.
authors.forename: Marc O
authors.initials: MO
authors.lastname: Anderson
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, CA 94143-0521, USA. Electronic address: Alan.Verkman@ucsf.edu.
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D061985:Madin Darby Canine Kidney Cells; D049990:Membrane Transport Modulators / Q000737:chemistry / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection; D014508:Urea / Q000378:metabolism*; D000096982:Urea Transporters
chemical_list: D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D013890:Thiourea; D014508:Urea; D000096982:Urea Transporters; C038983:1,3-dimethylthiourea
keywords: Diuretic; Kidney; Structure-activity relationships; Thiourea; Urea transporter