N-Methylanilide and N-methylbenzamide derivatives as phosphodiesterase 10A (PDE10A) inhibitors

Abstract PDE10A is a recently identified phosphodiesterase with a quite remarkable localization since the protein is abundant only in brain tissue. Based on this unique localization, research has focused extensively on using PDE10A modulators as a novel therapeutic approach for dysfunction in the basal ganglia circuit including Parkinson’s disease, Huntington’s disease, schizophrenia, addiction and obsessive compulsive disorder. Medicinal chemistry efforts identified the N -methyl- N -[4-(quinolin-2-ylmethoxy)-phenyl]-isonicotinamide ( 8 ) as a nanomolar PDE10A inhibitor. A subsequent Lead-optimization program identified analogous N -methylanilides and their corresponding N -methylbenzamides ( 29 ) as potent PDE10A inhibitors, concurrently some interesting and unexpected binding modes were identified.