Bioorganic & Medicinal Chemistry 2013-10-01

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

John Paul Kilburn, Jan Kehler, Morten Langgård, Mette N Erichsen, Sebastian Leth-Petersen, Mogens Larsen, Claus Tornby Christoffersen, Jacob Nielsen

Index: Bioorg. Med. Chem. 21(19) , 6053-62, (2013)

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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. Copyright © 2013 Elsevier Ltd. All rights reserved.