Synthesis and SAR study of novel tricyclic pyrazoles as potent phosphodiesterase 10A inhibitors

Eur J Med Chem. 2014 Sep 12:84:181-93. doi: 10.1016/j.ejmech.2014.07.020. Epub 2014 Jul 7.

Abstract

Novel pyrazolo[5,1-f][1,6]naphthyridines, pyrazolo[5,1-a][2,6]naphthyridines, pyrazolo[5,1-a][2,7]naphthyridines and pyrazolo[5,1-a]isoquinolines phenylimidazole/benzimidazole ethylene-linked were designed and synthesized for PDE10A interaction. An AgOTf and proline-cocatalyzed multicomponent methodology based on use of o-alkynylaldehydes, tosylhydrazide and ketones was developed and proved to be a convenient route for assembly of most of the novel tricyclic pyrazoles synthesized. Pyrazolo[5,1-f][1,6]naphthyridine 43 and 59, pyrazolo[5,1-a][2,6]naphthyridine 66, and pyrazolo[5,1-a][2,7]naphthyridine 42 showed the highest affinity for PDE10A enzyme (IC50 = 40, 42, 40, 55 nM, respectively).

Keywords: PDE10A inhibition; Structure–activity relationships; Tricyclic pyrazoles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Humans
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Structure
  • Phosphodiesterase Inhibitors / chemical synthesis*
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / metabolism*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Phosphodiesterase Inhibitors
  • Pyrazoles
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases