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

Article abstract of DOI:10.1016/j.ejmech.2014.07.020

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).