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Beschreibung

A cell-permeable triazolothienopyrimidine compound that acts as a reversible urea transporter B (UT-B)-selective inhibitor (IC50 = 10.3 and 25.1 nM against urea influx using human and mouse erythrocytes, respectively) by targeting a UT-B intracellular site in a urea-competitive manner, exhibiting little effect toward UT-A1, UT-A3, AQP1, CFTR, or TMEM16A channel activities and no cytotoxicity in MDCK cultures (100% viability after 24 h 10 µ,M inhibitor treatment). Shown to effectively decrease maximum urinary concentration (2.3- and 3.7-fold of basal [urea], respectively, with or without inhibitor, 300 µ,g/300 µ,l/mouse i.p.) and increase urination volume (236 vs.109 µ,l/4h, respectively, with or without inhibitor) from antidiuretic dDAVP- (1 µ,g/kg, administered 1 h after inhibitor) treated wild-type, but not UT-B-/-, mice in vivo. Despite its short half-life (t1/2 = 2.8 min) in in vitro rat hepatic microsomes stability tests, an average inhibitor concentration of 390 µ,M in blood can be reached in mice even 6 h after a single i.p. dose of 200 µ,l per animal., A cell-permeable triazolothienopyrimidine compound that acts as a reversible urea transporter B-selective inhibitor (IC50 = 10.3 and 25.1 nM against urea influx using human and mouse erythrocytes, respectively) by targeting a UT-B intracellular site in a urea-competitive manner, exhibiting little effect toward UT-A1, UT-A3, AQP1, CFTR, or TMEM16A channel activities. Shown to effectively decrease maximum urinary concentration and increase urination volume from antidiuretic dDAVP-treated wild-type, but not UT-B-/-, mice (300 µ,g/300 µ,l/mouse i.p.) in vivo.