Lars Kyhn Rasmussen

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

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.

PDE1A inhibition elicits cGMP-dependent relaxation of rat mesenteric arteries

PDE1, a subfamily of cyclic nucleotide PDEs consisting of three isoforms, PDE1A, PDE1B and PDE1C, has been implicated in the regulation of vascular tone. The PDE1 isoform(s) responsible for tone regulation is unknown. This study used isoform‐preferring PDE1 inhibitors, Lu AF58027, Lu AF64196, Lu AF66896 and Lu AF67897, to investigate the relative contribution of PDE1 isoforms to regulation of vascular tone.