Synthesis and evaluation of tetrahydropyrazolopyridine inhibitors of anion exchange protein SLC26A4 (pendrin)

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2119-2123. doi: 10.1016/j.bmcl.2019.07.003. Epub 2019 Jul 3.

Abstract

Pendrin is a transmembrane chloride/anion antiporter that is strongly upregulated in the airways in rhinoviral infection, asthma, cystic fibrosis and chronic rhinosinusitis. Based on its role in the regulation of airway surface liquid depth, pendrin inhibitors have potential indications for treatment of inflammatory airways diseases. Here, a completely regioselective route to tetrahydro-pyrazolopyridine pendrin inhibitors based on 1,3-diketone and substituted hydrazine condensation was been developed. Structure-activity relationships at the tetrahydropyridyl nitrogen were investigated using a focused library, establishing the privileged nature of N-phenyl ureas and improving inhibitor potency by greater than 2-fold.

Keywords: Anion transporter; Pendrin; Pyrazole; Regioselectivity; SLC26A4.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Mice
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology*
  • Rats, Inbred F344
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship
  • Sulfate Transporters / antagonists & inhibitors*

Substances

  • Pyrazoles
  • Pyridines
  • Slc26a4 protein, mouse
  • Small Molecule Libraries
  • Sulfate Transporters