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ID: ALA4145593
Journal: ACS Med Chem Lett
Title: Discovery of Orally Bioavailable Selective Inhibitors of the Sodium-Phosphate Cotransporter NaPi2a (SLC34A1).
Authors: Filipski KJ, Sammons MF, Bhattacharya SK, Panteleev J, Brown JA, Loria PM, Boehm M, Smith AC, Shavnya A, Conn EL, Song K, Weng Y, Facemire C, Jüppner H, Clerin V.
Abstract: Sodium-phosphate cotransporter 2a, or NaPi2a (SLC34A1), is a solute-carrier (SLC) transporter located in the kidney proximal tubule that reabsorbs glomerular-filtered phosphate. Inhibition of NaPi2a may enhance urinary phosphate excretion and correct maladaptive mineral and hormonal derangements associated with increased cardiovascular risk in chronic kidney disease-mineral and bone disorder (CKD-MBD). To date, only nonselective NaPi inhibitors have been described. Herein, we detail the discovery of the first series of selective NaPi2a inhibitors, resulting from optimization of a high-throughput screening hit. The oral PK profile of inhibitor PF-06869206 (6f) in rodents allows for the exploration of the pharmacology of selective NaPi2a inhibition.
CiteXplore: 29795756