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

Urea transporter
A (UT-A) isoforms encoded by the Slc14a2 gene are
expressed in kidney tubule epithelial cells, where they
facilitate urinary concentration. UT-A1 inhibition is predicted to
produce a unique salt-sparing diuretic action in edema and hyponatremia.
Here we report the discovery of 1,2,4-triazoloquinoxalines and the
analysis of 37 synthesized analogues. The most potent compound, 8ay, containing 1,2,4-triazolo­[4,3-a]­quinoxaline-substituted
benzenesulfonamide linked by an aryl ether, rapidly and reversibly
inhibited UT-A1 urea transport by a noncompetitive mechanism with
IC50 ≈ 150 nM; the IC50 was ∼2
μM for the related urea transporter UT-B encoded by the Slc14a1 gene. Molecular modeling suggested a putative binding
site on the UT-A1 cytoplasmic domain. In vitro metabolism showing
quinoxaline ring oxidation prompted the synthesis of metabolically
stable 7,8-difluoroquinoxaline analogue 8bl, which when
administered to rats produced marked diuresis and reduced urinary
osmolality. 8bl has substantially improved UT-A1 inhibition
potency and metabolic stability compared with prior compounds.