Design, synthesis, crystallographic studies, and preliminary biological appraisal of new substituted triazolo[4,3-b]pyridazin-8-amine derivatives as tankyrase inhibitors

J Med Chem. 2014 Mar 27;57(6):2807-12. doi: 10.1021/jm401356t. Epub 2014 Feb 24.

Abstract

Searching for selective tankyrases (TNKSs) inhibitors, a new small series of 6,8-disubstituted triazolo[4,3-b]piridazines has been synthesized and characterized biologically. Structure-based optimization of the starting hit compound NNL (3) prompted us to the discovery of 4-(2-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino)ethyl)phenol (12), a low nanomolar selective TNKSs inhibitor working as NAD isostere as ascertained by crystallographic analysis. Preliminary biological data candidate this new class of derivatives as a powerful pharmacological tools in the unraveling of TNKS implications in physiopathological conditions.

MeSH terms

  • Adenosine Diphosphate Ribose / metabolism
  • Chromatography, High Pressure Liquid
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indicators and Reagents
  • Luciferases / genetics
  • Mass Spectrometry
  • Models, Molecular
  • Molecular Conformation
  • Pyridazines / chemical synthesis*
  • Pyridazines / pharmacology*
  • Recombinant Proteins / drug effects
  • Structure-Activity Relationship
  • Tankyrases / antagonists & inhibitors*
  • Triazoles / chemical synthesis*
  • Triazoles / pharmacology*

Substances

  • 4-(2-(6-methyl-(1,2,4)triazolo(4,3-b)pyridazin-8-ylamino)ethyl)phenol
  • Enzyme Inhibitors
  • Indicators and Reagents
  • Pyridazines
  • Recombinant Proteins
  • Triazoles
  • Adenosine Diphosphate Ribose
  • Luciferases
  • Tankyrases
  • TNKS protein, human

Associated data

  • PDB/4M7B