Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1
Year: 2018
Type: article
Abstract: 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 IC 50 ≈ 150 nM; the IC 50 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.
Source: Journal of Medicinal Chemistry
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1259071441, G1906457638, G2415322494, Application of Novel Optical Methods to Cell Dynamics, Application of Novel Optical Methods to Cell Dynamics, Aquaporin-4 in NMO Optic Neuritis: Pathogenesis and New Therapies, G3730553470, Urea transport inhibitors as a new class of diuretics, Novel small-molecule therapies for CF, Translational Approaches to Develop Drug Therapy for Diarrhea
OpenAlex ID: W2794970377