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Discovery of 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent and orally bioavailable tissue-nonspecific alkaline phosphatase (TNAP) inhibitor.

Authors
  • Pinkerton, Anthony B1
  • Sergienko, Eduard2
  • Bravo, Yalda2
  • Dahl, Russell2
  • Ma, Chen-Ting2
  • Sun, Qing2
  • Jackson, Michael R2
  • Cosford, Nicholas D P3
  • Millán, José Luis4
  • 1 Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: [email protected]
  • 2 Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 3 NCI Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 4 Sanford Children's Health Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Jan 01, 2018
Volume
28
Issue
1
Pages
31–34
Identifiers
DOI: 10.1016/j.bmcl.2017.11.024
PMID: 29174347
Source
Medline
Keywords
License
Unknown

Abstract

Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme crucial for bone matrix mineralization via its ability to hydrolyze extracellular inorganic pyrophosphate (ePPi), a potent mineralization inhibitor, to phosphate (Pi). By the controlled hydrolysis of ePPi, TNAP maintains the correct ratio of Pi to ePPi and therefore enables normal skeletal and dental calcification. In other areas of the body low ePPi levels lead to the development of pathological soft-tissue calcification, which can progress to a number of disorders. TNAP inhibitors have been shown to prevent these processes via an increase of ePPi. Herein we describe the use of a whole blood assay to optimize a previously described series of TNAP inhibitors resulting in 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent, selective and oral bioavailable compound that robustly inhibits TNAP in vivo.

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