Design and Discovery of6-[(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),a Selective Brain Penetrant PDE9A Inhibitor for the Treatment of CognitiveDisorders

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 inhibitoridentified using parallel synthetic chemistry and structure-baseddrug design (SBDD) and has advanced into clinical trials. Selectivityfor PDE9A over other PDE family members was achieved by targetingkey residue differences between the PDE9A and PDE1C catalytic site.The physicochemical properties of the series were optimized to provideexcellent in vitro and in vivo pharmacokinetics properties in multiplespecies including humans. It has been reported to elevate centralcGMP levels in the brain and CSF of rodents. In addition, it exhibitsprocognitive activity in several rodent models and synaptic stabilizationin an amyloid precursor protein (APP) transgenic mouse model. Recentdisclosures from clinical trials confirm that it is well toleratedin humans and elevates cGMP in cerebral spinal fluid of healthy volunteers,confirming that it is a quality pharmacological tool for testing clinicalhypotheses in disease states associated with impairment of cGMP signalingor cognition. [ABSTRACT FROM AUTHOR]