Design and Discovery of 6‑[(3<i>S</i>,4<i>S</i>)‑4-Methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro‑2<i>H</i>‑pyran-4-yl)-1,5-dihydro‑4<i>H</i>‑pyrazolo[3,4‑<i>d</i>]pyrimidin-4-one (PF-04447943), a Selective Brain Penetrant PDE9A Inhibitor for the Treatment of Cognitive Disorders

6-[(3<i>S</i>,4<i>S</i>)-4-Methyl-1-(pyrimidin-2-ylmethyl)­pyrrolidin-3-yl]-1-(tetrahydro-2<i>H</i>-pyran-4-yl)-1,5-dihydro-4<i>H</i>-pyrazolo­[3,4-<i>d</i>]­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

Application of Structure-Based Drug Design and Parallel Chemistry to Identify Selective, Brain Penetrant, In Vivo Active Phosphodiesterase 9A Inhibitors

Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer’s disease. Our clinical candidate, PF-04447943 (<b>2</b>), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with <b>2</b> in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate <b>19</b> that demonstrated free brain/free plasma ≥1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF