GSK356278, a potent, selective, brain-penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species.
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.
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.
A Richard
AR
Rutter
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.).
Alessandro
A
Poffe
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.).
Palmina
P
Cavallini
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.).
T Gregg
TG
Davis
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.).
Jessica
J
Schneck
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.).
Michele
M
Negri
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.).
Elena
E
Vicentini
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.).
Dino
D
Montanari
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.).
Roberto
R
Arban
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.).
Frank A
FA
Gray
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.).
Ceri H
CH
Davies
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.).
Paul B
PB
Wren
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D002144:Callithrix; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000187:drug effects*; D003521:Cyclopropanes / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005289:Ferrets; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008252:Macaca fascicularis; D008297:Male; D018697:Nootropic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010069:Oxadiazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D058988:Phosphodiesterase 4 Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010842:Pica / Q000188:drug therapy; D051381:Rats; D020889:Rolipram / Q000494:pharmacology; D013844:Thiazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
C000590928:5-(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; D000631:Aminopyridines; D014151:Anti-Anxiety Agents; D001549:Benzamides; D003521:Cyclopropanes; D007527:Isoenzymes; D018697:Nootropic Agents; D010069:Oxadiazoles; D058988:Phosphodiesterase 4 Inhibitors; D013844:Thiazoles; C424423:Roflumilast; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; D020889:Rolipram