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

  • Bioorg Med Chem Lett. 2018 Jan 1;28(1):31-34. doi: 10.1016/j.bmcl.2017.11.024.
Anthony B Pinkerton  1 ,  Eduard Sergienko  2 ,  Yalda Bravo  2 ,  Russell Dahl  2 ,  Chen-Ting Ma  2 ,  Qing Sun  2 ,  Michael R Jackson  2 ,  Nicholas D P Cosford  3 ,  José Luis Millán  4
Affiliations
  • 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.
PMID: 29174347 DOI: 10.1016/j.bmcl.2017.11.024
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.

Keywords
Calcification; Enzyme inhibitors; Inhibitors; TNAP; Tissue nonspecific alkaline phosphatase.
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