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Positiveallosteric modulators (“potentiators”) ofα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)receptors (AMPAR) enhance excitatory neurotransmission and may improvethe cognitive deficits associated with various neurological disorders.The dihydroisoxazole (DHI) series of AMPAR potentiators describedherein originated from the identification of 7by a high-throughputfunctional activity screen using mouse embryonic stem (mES) cell-derivedneuronal precursors. Subsequent structure-based drug design usingX-ray crystal structures of the ligand-binding domain of human GluA2led to the discovery of both PF-04725379 (11), whichin tritiated form became a novel ligand for characterizing the bindingaffinities of subsequent AMPAR potentiators in rat brain homogenate,and PF-04701475 (8a), a prototype used to explore AMPAR-mediatedpharmacology in vivo. Lead series optimization provided 16a, a functionally potent compound lacking the potentially bioactivatableaniline within 8a, but retaining desirable in vitro ADMEproperties. [ABSTRACT FROM AUTHOR]

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]

Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability. [ABSTRACT FROM AUTHOR]

Toaccelerate the discovery of novel small molecule central nervoussystem (CNS) positron emission tomography (PET) ligands, we aimedto define a property space that would facilitate ligand design andprioritization, thereby providing a higher probability of successfor novel PET ligand development. Toward this end, we built a databaseconsisting of 62 PET ligands that have successfully reached the clinicand 15 radioligands that failed in late-stage development as negativecontrols. A systematic analysis of these ligands identified a setof preferred parameters for physicochemical properties, brain permeability,and nonspecific binding (NSB). These preferred parameters have subsequentlybeen applied to several programs and have led to the successful developmentof novel PET ligands with reduced resources and timelines. This strategyis illustrated here by the discovery of the novel phosphodiesterase2A (PDE2A) PET ligand 4-(3-[18F]fluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazine,[18F]PF-05270430 (5). [ABSTRACT FROM AUTHOR]

Phosphodiesterase 9A inhibitors have shown activity inpreclinicalmodels of cognition with potential application as novel therapiesfor treating Alzheimer’s disease. Our clinical candidate, PF-04447943(2), demonstrated acceptable CNS permeability in ratswith modest asymmetry between central and peripheral compartments(free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemicalproperties outside the range associated with traditional CNS drugs.To address the potential risk of restricted CNS penetration with 2in human clinical trials, we sought to identify a preclinicalcandidate with no asymmetry in rat brain penetration and that couldadvance into development. Merging the medicinal chemistry strategiesof structure-based design with parallel chemistry, a novel seriesof PDE9A inhibitors was identified that showed improved selectivityover PDE1C. Optimization afforded preclinical candidate 19that demonstrated free brain/free plasma ≥1 in rat and reducedmicrosomal clearance along with the ability to increase cyclic guanosinemonophosphosphate levels in rat CSF. [ABSTRACT FROM AUTHOR]