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GSK356278, a potent, selective, brain-penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species.
J Pharmacol Exp Ther. 2014 Jul; 350(1):153-63.JP

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 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.

Authors+Show Affiliations

GlaxoSmithKline, Discovery Medicine, Stevenage, Herts, United Kingdom (F.A.G., P.B.W.); GlaxoSmithKline, Neural Pathways Discovery Performance Unit, Biopolis, Singapore (A.R.R., C.H.D.); GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Verona, Italy (A.P., P.C., M.N., E.V., D.M., R.A.); GlaxoSmithKline, Molecular Discovery Research, Collegeville, Pennsylvania (J.S.); and GlaxoSmithKline, Respiratory Centre of Excellence for Drug Discovery, King of Prussia, Pennsylvania (T.G.D.) Richard.a.rutter@gsk.com.GlaxoSmithKline, Discovery Medicine, Stevenage, Herts, United Kingdom (F.A.G., P.B.W.); GlaxoSmithKline, Neural Pathways Discovery Performance Unit, Biopolis, Singapore (A.R.R., C.H.D.); GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Verona, Italy (A.P., P.C., M.N., E.V., D.M., R.A.); GlaxoSmithKline, Molecular Discovery Research, Collegeville, Pennsylvania (J.S.); and GlaxoSmithKline, Respiratory Centre of Excellence for Drug Discovery, King of Prussia, Pennsylvania (T.G.D.).GlaxoSmithKline, Discovery Medicine, Stevenage, Herts, United Kingdom (F.A.G., P.B.W.); GlaxoSmithKline, Neural Pathways Discovery Performance Unit, Biopolis, Singapore (A.R.R., C.H.D.); GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Verona, Italy (A.P., P.C., M.N., E.V., D.M., R.A.); GlaxoSmithKline, Molecular Discovery Research, Collegeville, Pennsylvania (J.S.); and GlaxoSmithKline, Respiratory Centre of Excellence for Drug Discovery, King of Prussia, Pennsylvania (T.G.D.).GlaxoSmithKline, Discovery Medicine, Stevenage, Herts, United Kingdom (F.A.G., P.B.W.); GlaxoSmithKline, Neural Pathways Discovery Performance Unit, Biopolis, Singapore (A.R.R., C.H.D.); GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Verona, Italy (A.P., P.C., M.N., E.V., D.M., R.A.); GlaxoSmithKline, Molecular Discovery Research, Collegeville, Pennsylvania (J.S.); and GlaxoSmithKline, Respiratory Centre of Excellence for Drug Discovery, King of Prussia, Pennsylvania (T.G.D.).GlaxoSmithKline, Discovery Medicine, Stevenage, Herts, United Kingdom (F.A.G., P.B.W.); GlaxoSmithKline, Neural Pathways Discovery Performance Unit, Biopolis, Singapore (A.R.R., C.H.D.); GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Verona, Italy (A.P., P.C., M.N., E.V., D.M., R.A.); GlaxoSmithKline, Molecular Discovery Research, Collegeville, Pennsylvania (J.S.); and GlaxoSmithKline, Respiratory Centre of Excellence for Drug Discovery, King of Prussia, Pennsylvania (T.G.D.).GlaxoSmithKline, Discovery Medicine, Stevenage, Herts, United Kingdom (F.A.G., P.B.W.); GlaxoSmithKline, Neural Pathways Discovery Performance Unit, Biopolis, Singapore (A.R.R., C.H.D.); GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Verona, Italy (A.P., P.C., M.N., E.V., D.M., R.A.); GlaxoSmithKline, Molecular Discovery Research, Collegeville, Pennsylvania (J.S.); and GlaxoSmithKline, Respiratory Centre of Excellence for Drug Discovery, King of Prussia, Pennsylvania (T.G.D.).GlaxoSmithKline, Discovery Medicine, Stevenage, Herts, United Kingdom (F.A.G., P.B.W.); GlaxoSmithKline, Neural Pathways Discovery Performance Unit, Biopolis, Singapore (A.R.R., C.H.D.); GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Verona, Italy (A.P., P.C., M.N., E.V., D.M., R.A.); GlaxoSmithKline, Molecular Discovery Research, Collegeville, Pennsylvania (J.S.); and GlaxoSmithKline, Respiratory Centre of Excellence for Drug Discovery, King of Prussia, Pennsylvania (T.G.D.).GlaxoSmithKline, Discovery Medicine, Stevenage, Herts, United Kingdom (F.A.G., P.B.W.); GlaxoSmithKline, Neural Pathways Discovery Performance Unit, Biopolis, Singapore (A.R.R., C.H.D.); GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Verona, Italy (A.P., P.C., M.N., E.V., D.M., R.A.); GlaxoSmithKline, Molecular Discovery Research, Collegeville, Pennsylvania (J.S.); and GlaxoSmithKline, Respiratory Centre of Excellence for Drug Discovery, King of Prussia, Pennsylvania (T.G.D.).GlaxoSmithKline, Discovery Medicine, Stevenage, Herts, United Kingdom (F.A.G., P.B.W.); GlaxoSmithKline, Neural Pathways Discovery Performance Unit, Biopolis, Singapore (A.R.R., C.H.D.); GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Verona, Italy (A.P., P.C., M.N., E.V., D.M., R.A.); GlaxoSmithKline, Molecular Discovery Research, Collegeville, Pennsylvania (J.S.); and GlaxoSmithKline, Respiratory Centre of Excellence for Drug Discovery, King of Prussia, Pennsylvania (T.G.D.).GlaxoSmithKline, Discovery Medicine, Stevenage, Herts, United Kingdom (F.A.G., P.B.W.); GlaxoSmithKline, Neural Pathways Discovery Performance Unit, Biopolis, Singapore (A.R.R., C.H.D.); GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Verona, Italy (A.P., P.C., M.N., E.V., D.M., R.A.); GlaxoSmithKline, Molecular Discovery Research, Collegeville, Pennsylvania (J.S.); and GlaxoSmithKline, Respiratory Centre of Excellence for Drug Discovery, King of Prussia, Pennsylvania (T.G.D.).GlaxoSmithKline, Discovery Medicine, Stevenage, Herts, United Kingdom (F.A.G., P.B.W.); GlaxoSmithKline, Neural Pathways Discovery Performance Unit, Biopolis, Singapore (A.R.R., C.H.D.); GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Verona, Italy (A.P., P.C., M.N., E.V., D.M., R.A.); GlaxoSmithKline, Molecular Discovery Research, Collegeville, Pennsylvania (J.S.); and GlaxoSmithKline, Respiratory Centre of Excellence for Drug Discovery, King of Prussia, Pennsylvania (T.G.D.).GlaxoSmithKline, Discovery Medicine, Stevenage, Herts, United Kingdom (F.A.G., P.B.W.); GlaxoSmithKline, Neural Pathways Discovery Performance Unit, Biopolis, Singapore (A.R.R., C.H.D.); GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Verona, Italy (A.P., P.C., M.N., E.V., D.M., R.A.); GlaxoSmithKline, Molecular Discovery Research, Collegeville, Pennsylvania (J.S.); and GlaxoSmithKline, Respiratory Centre of Excellence for Drug Discovery, King of Prussia, Pennsylvania (T.G.D.).

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24784567

Citation

Rutter, A Richard, et al. "GSK356278, a Potent, Selective, Brain-penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-enhancing Effects Without Inducing Side Effects in Preclinical Species." The Journal of Pharmacology and Experimental Therapeutics, vol. 350, no. 1, 2014, pp. 153-63.
Rutter AR, Poffe A, Cavallini P, et al. GSK356278, a potent, selective, brain-penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species. J Pharmacol Exp Ther. 2014;350(1):153-63.
Rutter, A. R., Poffe, A., Cavallini, P., Davis, T. G., Schneck, J., Negri, M., Vicentini, E., Montanari, D., Arban, R., Gray, F. A., Davies, C. H., & Wren, P. B. (2014). GSK356278, a potent, selective, brain-penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species. The Journal of Pharmacology and Experimental Therapeutics, 350(1), 153-63. https://doi.org/10.1124/jpet.114.214155
Rutter AR, et al. GSK356278, a Potent, Selective, Brain-penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-enhancing Effects Without Inducing Side Effects in Preclinical Species. J Pharmacol Exp Ther. 2014;350(1):153-63. PubMed PMID: 24784567.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GSK356278, a potent, selective, brain-penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species. AU - Rutter,A Richard, AU - Poffe,Alessandro, AU - Cavallini,Palmina, AU - Davis,T Gregg, AU - Schneck,Jessica, AU - Negri,Michele, AU - Vicentini,Elena, AU - Montanari,Dino, AU - Arban,Roberto, AU - Gray,Frank A, AU - Davies,Ceri H, AU - Wren,Paul B, Y1 - 2014/04/30/ PY - 2014/5/3/entrez PY - 2014/5/3/pubmed PY - 2014/8/27/medline SP - 153 EP - 63 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 350 IS - 1 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/24784567/GSK356278_a_potent_selective_brain_penetrant_phosphodiesterase_4_inhibitor_that_demonstrates_anxiolytic_and_cognition_enhancing_effects_without_inducing_side_effects_in_preclinical_species_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=24784567 DB - PRIME DP - Unbound Medicine ER -