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.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Cognition/drug effects , Neuronal Plasticity/drug effects , Phosphodiesterase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidinones/pharmacology , Synapses/drug effects , Synapses/enzymology , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Animals , CHO Cells , Cognition/physiology , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Female , HEK293 Cells , Hippocampus/drug effects , Hippocampus/enzymology , Humans , Macaca mulatta , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Neuronal Plasticity/physiology , Phosphodiesterase Inhibitors/metabolism , Pyrazoles/metabolism , Pyrimidinones/metabolism , Rats , Rats, Sprague-Dawley , Rats, WistarABSTRACT
The title compound, the condensation product of sulfur dichloride and 1,5-cyclooctadiene, is a reliable acceptor of a wide variety of heteroatom nucleophiles, sometimes in reversible fashion. Optical resolution of the core structure has been achieved and preserved in succeeding transformations. The high reactivity and reliable stereochemical control afforded by this system illustrates the power of neighboring-group participation by the sulfur center.
Subject(s)
Alkanes/chemistry , Bridged Bicyclo Compounds/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular StructureABSTRACT
The complete set of the 4'-aza analogues of 2',3'-dideoxynucleosides was synthesized by cycloaddition of N-tetrahydropiranyl or N-trityl methylene nitrones on suitably protected vinyl nucleobases. The convertible nucleoside approach was used in the preparation of cytosine and 5-methyl cytosine analogues.
