title: 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.
authors: H. Lundbeck A/S, Department of Medicinal Chemistry, DK-2500 Valby, Denmark. jpk@lundbeck.com
authors: John Paul
authors: JP
authors: Kilburn
authors: Jan
authors: J
authors: Kehler
authors: Morten
authors: M
authors: Langgård
authors: Mette N
authors: MN
authors: Erichsen
authors: Sebastian
authors: S
authors: Leth-Petersen
authors: Mogens
authors: M
authors: Larsen
authors: Claus Tornby
authors: CT
authors: Christoffersen
authors: Jacob
authors: J
authors: Nielsen
mesh_terms: D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; D001549:Benzamides; D010726:Phosphodiesterase Inhibitors; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; C038530:N-methylbenzamide
keywords: Antipsychotics; MPO; Molecular modeling; Phosphodieasterase 10A inhibitors; Schizophrenia