GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species

Abstract

Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. Despite the registration of the first PDE4 inhibitor, roflumilast, for the treatment of chronic obstructive pulmonary disease, the therapeutic potential of PDE4 inhibitors in neurologic diseases has never been fulfilled in the clinic due to severe doselimiting side effects such as nausea and vomiting. In this study, we describe the detailed pharmacological characterization of GSK356278 [5-(5-((2,4-dimethylthiazol-5-yl)methyl)-1,3,4-oxadiazol-2-yl)-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo [3,4-b] pyridin-4-amine], a potent, selective, and brain-penetrant PDE4 inhibitor that shows a superior therapeutic index to both rolipram and roflumilast in various preclinical species and has potential for further development in the clinic for the treatment of psychiatric and neurologic diseases. GSK356278 inhibited PDE4B enzyme activity with a pIC 50 of 8.8 and bound to the high-affinity rolipram binding site with a pIC 50 of 8.6. In preclinical models, the therapeutic index as defined in a rodent lung inflammation model versus rat pica feeding was .150 compared with 0.5 and 6.4 for rolipram and roflumilast, respectively. In a model of anxiety in common marmosets, the therapeutic index for GSK356278 was .10 versus ,1 for rolipram. We also demonstrate that GSK356278 enhances performance in a model of executive function in cynomolgus macaques with no adverse effects, a therapeutic profile that supports further evaluation of GSK356278 in a clinical setting.

Phosphodiesterase-4 inhibitors ameliorates cognitive deficits in deoxycorticosterone acetate induced hypertensive rats via cAMP/CREB signaling system

“…All these subtypes are selective for cAMP (Rutter et al, 2014). In the present study, the authors have demonstrated the subtype -specific inhibitory properties of rolipram and roflumilast on PDE-4, of which PDE-4B and PDE-4D were significantly inhibited.…”

A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram

“…There has been no clinical data to show the improvement of cognition by PDE4 inhibitors in clinical settings although several lines of research using animal models suggest that PDE4 inhibition could improve some cognitive domains such as executive functions and memory [32,33]. Regarding PDE4 subtypes, PDE4D is considered to be related to cognitive improvement [34,35] while PDE4B is also considered to be involved in the cognitive function [36].…”

Assessment of curated phenotype mining in neuropsychiatric disorder literature

“…PDE4 (A to D) inhibitors are used in the therapy of neurological disorders because of their anti-depressant and cognition enhancing effects, mediated by the elevation of intracellular cAMP and increased production of norepinephrine [22]. According to the similarity in phenotype associations between disorders (Fig.…”