Characterisation of Lu AF33241: A novel, brain-penetrant, dual inhibitor of phosphodiesterase (PDE) 2A and PDE10A

• Published in: European journal of pharmacology Vol. 761; pp. 79 - 85
• Main Authors: Redrobe, John P., Rasmussen, Lars K., Christoffersen, Claus T., Bundgaard, Christoffer, Jørgensen, Morten
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.08.2015
• Subjects: Animals; Antipsychotic; Antipsychotic Agents - metabolism; Antipsychotic Agents - pharmacology; Antipsychotic Agents - toxicity; Avoidance Learning - drug effects; Behavior, Animal - drug effects; Blood-Brain Barrier - metabolism; Capillary Permeability; Catalepsy - chemically induced; Cognition; Cognition - drug effects; Cyclic Nucleotide Phosphodiesterases, Type 2 - antagonists & inhibitors; Cyclic Nucleotide Phosphodiesterases, Type 2 - metabolism; Exploratory Behavior - drug effects; Humans; Inhibitor; Male; Motor Activity - drug effects; PDE10A; PDE2A; Phosphodiesterase Inhibitors - metabolism; Phosphodiesterase Inhibitors - pharmacology; Phosphodiesterase Inhibitors - toxicity; Phosphoric Diester Hydrolases - metabolism; Quinoxalines - metabolism; Quinoxalines - pharmacology; Rats, Sprague-Dawley; Rats, Wistar; Recognition (Psychology) - drug effects; Schizophrenia; Triazoles - metabolism; Triazoles - pharmacology; Schizophrenia; Antipsychotic; Inhibitor; Cognition; PDE10A; PDE2A
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2015.04.040

Here, we present a preliminary pharmacological characterisation of Lu AF33241, a novel, brain penetrant phosphodiesterase inhibitor of (PDE) 2A and 10A tool compound, in in vitro/in vivo assays indicative of PDE2A and/or PDE10A inhibition, and in vivo models/assays relevant to cognitive processing and antipsychotic-like activity. An assay was also included to investigate potential effects on motor activity. The in vitro selectivity of Lu AF33241 was determined against a panel of PDE enzymes. Lu AF33241 potently inhibited both full-length recombinant hPDE2A (Ki=4.2nM) and hPDE10A (Ki=42nM). The compound moderately inhibited both hPDE1C (Ki=1200nM), hPDE7B (Ki=890nM), and hPDE11A (Ki=1800nM). Lu AF33241 displayed a Ki above 5000nM against all other tested members of the PDE family. Albeit within a narrow dose range, Lu AF33241 attenuated sub-chronic phencyclidine-induced deficits in novel object recognition (3 and 10mg/kg), displayed antipsychotic-like activity in the conditioned avoidance response paradigm (10mg/kg), and did not induce catalepsy within a dose-range of 2–6mg/kg. Further catalepsy studies are needed to investigate a predictive safety window. Lu AF33241 represents a novel PDE2A/PDE10A inhibitor tool compound that may serve to further the understanding of the roles played by these enzymes in various CNS disorders.