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

  • ACS Med Chem Lett. 2018 Apr 12;9(5):440-445. doi: 10.1021/acsmedchemlett.8b00013.
Kevin J Filipski  1 ,  Matthew F Sammons  1 ,  Samit K Bhattacharya  1 ,  Jane Panteleev  2 ,  Janice A Brown  2 ,  Paula M Loria  2 ,  Markus Boehm  1 ,  Aaron C Smith  2 ,  Andre Shavnya  2 ,  Edward L Conn  2 ,  Kun Song  1 ,  Yan Weng  1 ,  Carie Facemire  1 ,  Harald Jüppner  3 ,  Valerie Clerin  1
Affiliations
  • 1. Pfizer Worldwide Research & Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • 2. Pfizer Worldwide Research & Development, 558 Eastern Point Road, Groton, Connecticut 06340, United States.
  • 3. Endocrine Unit and Pediatric Nephrology Unit, Thier 10, Massachusetts General Hospital and Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114, United States.
PMID: 29795756 DOI: 10.1021/acsmedchemlett.8b00013
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.

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