2. Academic Validation
  3. Discovery of Orally Bioavailable Selective Inhibitors of the Sodium-Phosphate Cotransporter NaPi2a (SLC34A1)

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

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.

Figures
Products