Synthesis and biological evaluation of 7-(aminoalkyl)pyrazolo[1,5-a]pyrimidine derivatives as cathepsin K inhibitors

Bioorg Chem. 2019 Mar:84:226-238. doi: 10.1016/j.bioorg.2018.11.029. Epub 2018 Nov 19.

Abstract

A series of novel 7-aminoalkyl substituted pyrazolo[1,5-a]pyrimidine derivatives were synthesized and tested for inhibition of cathepsin K. The synthetic methodology comprises cyclization of 5-aminopyrazoles with N-Boc-α-amino acid-derived ynones followed by transformation of the ester and the Boc-amino functions. It allows for easy diversification of the pyrazolo[1,5-a]pyrimidine scaffold at various positions. Molecular docking studies with pyrazolo[1,5-a]pyrimidine derivatives were also performed to elucidate the binding mode in the active site of cathepsin K. The synthesized compounds exhibited moderate inhibition activity (Ki ≥ 77 μM).

Keywords: Cathepsin K; Cyclisation; Enzyme inhibition; Molecular docking; Pyrazoles; Pyrazolo[1,5-a]pyrimidines; Ynones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Cathepsin K / antagonists & inhibitors*
  • Cathepsin K / metabolism
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / metabolism
  • Humans
  • Molecular Conformation
  • Molecular Docking Simulation
  • Pyrazoles / chemistry*
  • Pyrazoles / metabolism
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Pyrazoles
  • Pyrimidines
  • pyrazolo(1,5-a)pyrimidine
  • Cathepsin K