Sintesi, studi SAR e valutazione biologica di nuove molecole a piattaforma naftiridinica quali inibitori dell'enzima fosfodiesterasi 10A

Phosphodiesterase 10A (PDE10A) is a basal ganglia specific hydrolase, which plays an essential role in regulating cAMP/PKA and cGMP/PKG signalling cascades.PDE10A is a relatively newly identified phosphodiesterase. In the brain, the enzyme is predominantly expressed in medium spiny neurons of the striatum, making it an interesting target for the treatment of central nervous system disorders associated to dysfunction in the basal ganglia circuit.Recently, a series of pyrazolo-quinazolines and pyrazolo-naphthyridines with good IC50 values and high selectivity against other PDE isoforms has been developed. In this context, we have realized a new series of 1,6-naphthyridines, 2,6-naphthyridines, 2,7-naphthyridines and 1,7-naphtyridines, with various substitutions, as new potential inhibitors of Phosphodiesterase 10A. Among them, 18Ac showed the highest affinity for PDE10A (IC50: 24 nM).