PT  - JOURNAL ARTICLE
AU  - A. Richard Rutter
AU  - Alessandro Poffe
AU  - Palmina Cavallini
AU  - T. Gregg Davis
AU  - Jessica Schneck
AU  - Michele Negri
AU  - Elena Vicentini
AU  - Dino Montanari
AU  - Roberto Arban
AU  - Frank A. Gray
AU  - Ceri H. Davies
AU  - Paul B. Wren
TI  - GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species
AID  - 10.1124/jpet.114.214155
DP  - 2014 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 153--163
VI  - 350
IP  - 1
4099  - http://jpet.aspetjournals.org/content/350/1/153.short
4100  - http://jpet.aspetjournals.org/content/350/1/153.full
SO  - J Pharmacol Exp Ther2014 Jul 01; 350
AB  - 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 dose-limiting 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 pIC50 of 8.8 and bound to the high-affinity rolipram binding site with a pIC50 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.