1082744-20-4

Basic information

• Product Name: PF 04447943
• Synonyms: PF 04447943;PF-04447943;1,5-Dihydro-6-[(3S,4S)-4-methyl-1-(2-pyrimidinylmethyl)-3-pyrrolidinyl]-1-(tetrahydro-2H-pyran-4-yl)-4H-pyrazolo[3,4-d]pyrimidin-4-one;PF 4447943;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;6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(oxan-4-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-one;EOS-62041
• CAS NO: 1082744-20-4
• Molecular Formula: C₂₀H₂₅N₇O₂
• Molecular Weight: 395.4582
• Mol File: 1082744-20-4.mol
• Article Data: 3

Chemical Properties

• Boiling Point: 599.8±60.0 °C(Predicted)
• Appearance: /
• Density: 1.52±0.1 g/cm3(Predicted)
• Storage Temp.: -20C
• Solubility: Soluble in DMSO
• PKA: 7.22±0.60(Predicted)
• CAS DataBase Reference: PF 04447943(CAS DataBase Reference)
• NIST Chemistry Reference: PF 04447943(1082744-20-4)
• EPA Substance Registry System: PF 04447943(1082744-20-4)

Safety Data

• Hazardous Substances Data: 1082744-20-4(Hazardous Substances Data)

Usage

Biological Activity

pf-04447943 is a potent and selective inhibitor of pde9 [1].phosphodiesterase 9 (pde9) selectively degrades cgmp and limits the cgmp-mediated signal transduction which occurs following glutamate binding to nmda receptors. pde9 in cortex and hippocampus of rodents and humans play an important role in memory and learning [1].pf-04447943 have high affinity with 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. in cultured hippocampal neurons, pf-04447943 (30-100 nm) significantly increased neurite outgrowth and synapse formation. also, pf-04447943 (100 nm) significantly facilitated hippocampal slice ltp evoked by a weak tetanic stimulus [1].in mice model, pf-04447943 (1 mg/kg) significantly reduced the time spent interacting with the female mouse during the second encounter 24 h later compared to the first encounter, which suggested that pf-04447943 enhanced recognition memory. while, pf-04447943 (3 or 10 mg/kg) didn’t change the interaction times for each encounter. these results suggested that pf-04447943 enhanced memory with an inverted u-shaped dose-response efficacy curve [1].

references

[1]hutson ph, finger en, magliaro bc, et al. 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. neuropharmacology, 2011, 61(4): 665-676.

Upstream product

• 936643-80-0 2-(chloromethyl)pyrimidine hydrogen chloride 
• 29943-42-8 Tetrahydro-4H-pyran-4-one 
• 693287-79-5 N’-(tetrahydropyran-4-yl)hydrazinecarboxylic acid tert-butyl ester 
• 1082745-49-0 5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carbonitrile 
• 1082745-50-3 5-amino-1-(tetrahydropyran-4-yl)-1H-pyrazole-4-carboxylic acid amide 
• 1082743-70-1 6-((3S,4S)-1-benzyl-4-methylpyrrolidin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 

Relevant articles and documents

Design and discovery of 6-[(3 s,4 s)-4-methyl-1-(pyrimidin-2-ylmethyl) pyrrolidin-3-yl]-1-(tetrahydro-2 h -pyran-4-yl)-1,5-dihydro-4 h -pyrazolo[3,4- d ]pyrimidin-4-one (PF-04447943), a selective brain penetrant pde9a inhibitor for the treatment of cognitive disorders

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 (PF-04447943) is a novel PDE9A inhibitor identified using parallel synthetic chemistry and structure-based drug design (SBDD) and has advanced into clinical trials. Selectivity for PDE9A over other PDE family members was achieved by targeting key residue differences between the PDE9A and PDE1C catalytic site. The physicochemical properties of the series were optimized to provide excellent in vitro and in vivo pharmacokinetics properties in multiple species including humans. It has been reported to elevate central cGMP levels in the brain and CSF of rodents. In addition, it exhibits procognitive activity in several rodent models and synaptic stabilization in an amyloid precursor protein (APP) transgenic mouse model. Recent disclosures from clinical trials confirm that it is well tolerated in humans and elevates cGMP in cerebral spinal fluid of healthy volunteers, confirming that it is a quality pharmacological tool for testing clinical hypotheses in disease states associated with impairment of cGMP signaling or cognition.

AMINO-HETEROCYCLIC COMPOUNDS

The invention provides PDE9-inhibiting compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein R, R1, R2 and R3 are as defined herein. Pharmaceutical compositions containing the compounds of Formul