title: The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) enhances synaptic plasticity and cognitive function in rodents.
abstract: Inhibition of phosphodiesterase 9 (PDE9) has been reported to enhance rodent cognitive function and may represent a potential novel approach to improving cognitive dysfunction in Alzheimer's disease. PF-04447943, (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one), a recently described PDE9 inhibitor, was found to have high affinity (Ki of 2.8, 4.5 and 18 nM) for human, rhesus and rat recombinant PDE9 respectively and high selectivity for PDE9 versus PDEs1-8 and 10-11. PF-04447943 significantly increased neurite outgrowth and synapse formation (as indicated by increased synapsin 1 expression) in cultured hippocampal neurons at low (30-100 nM) but not high (300-1000 nM) concentrations. PF-04447943 significantly facilitated hippocampal slice LTP evoked by a weak tetanic stimulus at a concentration of 100 nM but failed to affect response to the weak tetanus at either 30 or 300 nM, or the LTP produced by a theta burst stimulus. Systemic administration of PF-04447943 (1-30 mg/kg p.o.) dose-dependently increased cGMP in the cerebrospinal fluid 30 min after administration indicating target engagement in the CNS of rats. PF-04447943 (1-3 mg/kg p.o.) significantly improved cognitive performance in three rodent cognition assays (mouse Y maze spatial recognition memory model of natural forgetting, mouse social recognition memory model of natural forgetting and rat novel object recognition with a scopolamine deficit). When administered at a dose of 3 mg/kg p.o., which improved performance in novel object recognition, PF-04447943 significantly increased phosphorylated but not total GluR1 expression in rat hippocampal membranes. Collectively these data indicate that PF-04447943 is a potent, selective brain penetrant PDE9 inhibitor that increased indicators of hippocampal synaptic plasticity and improved cognitive function in a variety of cognition models in both rats and mice. Results with PF-04447943 are consistent with previously published findings using a structurally diverse PDE9 inhibitor, BAY73-6199, and further support the suggestion that PDE9 inhibition may represent a novel approach to the palliative remediation of cognitive dysfunction.
authors.affiliation: Merck & Co., Inc., Department of Neuroscience, West Point, PA 19486, USA. Peter_Hutson@merck.com
authors.forename: P H
authors.initials: PH
authors.lastname: Hutson
authors.forename: E N
authors.initials: EN
authors.lastname: Finger
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authors.initials: BC
authors.lastname: Magliaro
authors.forename: S M
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authors.lastname: Smith
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authors.lastname: Converso
authors.forename: P E
authors.initials: PE
authors.lastname: Sanderson
authors.forename: D
authors.initials: D
authors.lastname: Mullins
authors.forename: L A
authors.initials: LA
authors.lastname: Hyde
authors.forename: B K
authors.initials: BK
authors.lastname: Eschle
authors.forename: Z
authors.initials: Z
authors.lastname: Turnbull
authors.forename: H
authors.initials: H
authors.lastname: Sloan
authors.forename: M
authors.initials: M
authors.lastname: Guzzi
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Wang
authors.forename: D
authors.initials: D
authors.lastname: Rindgen
authors.forename: R
authors.initials: R
authors.lastname: Mazzola
authors.forename: J A
authors.initials: JA
authors.lastname: Vivian
authors.forename: D
authors.initials: D
authors.lastname: Eddins
authors.forename: J M
authors.initials: JM
authors.lastname: Uslaner
authors.forename: R
authors.initials: R
authors.lastname: Bednar
authors.forename: C
authors.initials: C
authors.lastname: Gambone
authors.forename: W
authors.initials: W
authors.lastname: Le-Mair
authors.forename: M J
authors.initials: MJ
authors.lastname: Marino
authors.forename: N
authors.initials: N
authors.lastname: Sachs
authors.forename: G
authors.initials: G
authors.lastname: Xu
authors.forename: S
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authors.lastname: Parmentier-Batteur
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology*; D011744:Pyrimidinones / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects* / Q000201:enzymology*
chemical_list: C572323:6-(4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo(3,4-d)pyrimidin-4-one; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011744:Pyrimidinones; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C116137:PDE9A protein, human