N-Methylanilide and N-methylbenzamide derivatives as phosphodiesterase 10A (PDE10A) inhibitors |
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Authors: | John Paul Kilburn Jan Kehler Morten Langgård Mette N Erichsen Sebastian Leth-Petersen Mogens Larsen Claus Tornby Christoffersen Jacob Nielsen |
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Institution: | 1. H. Lundbeck A/S, Department of Medicinal Chemistry, DK-2500 Valby, Denmark;2. Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark;3. LEO Pharma A/S, Department of Medicinal Chemistry, DK-2750 Ballerup, Denmark;4. H. Lundbeck A/S, Department of Molecular Pharmacology, DK-2500 Valby, Denmark;5. H. Lundbeck A/S, Department of Molecular Neurobiology, DK-2500 Valby, Denmark |
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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. |
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Keywords: | Phosphodieasterase 10A inhibitors Schizophrenia Antipsychotics Molecular modeling MPO |
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