Discovery of Orally Bioavailable Selective Inhibitors of the Sodium-Phosphate Cotransporter NaPi2a (SLC34A1)

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2018 May 26

PMID 29795756

Citations 12

Authors

Kevin J Filipski

Matthew F Sammons

Samit K Bhattacharya

Jane Panteleev

Janice A Brown

Paula M Loria

Markus Boehm

Aaron C Smith

Andre Shavnya

Edward L Conn

Kun Song

Yan Weng

Carie Facemire

Harald Juppner

Valerie Clerin

Affiliations

Soon will be listed here.

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 () in rodents allows for the exploration of the pharmacology of selective NaPi2a inhibition.

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