Discovery of an Orally Bioavailable, Brain-Penetrating, in Vivo Active Phosphodiesterase 2A Inhibitor Lead Series for the Treatment of Cognitive Disorders

Herein,
we describe the discovery of a potent, selective, brain-penetrating,
in vivo active phosphodiesterase (PDE) 2A inhibitor lead series. To
identify high-quality leads suitable for optimization and enable validation
of the physiological function of PDE2A in vivo, structural modifications
of the high-throughput screening hit 18 were performed.
Our lead generation efforts revealed three key potency-enhancing functionalities
with minimal increases in molecular weight (MW) and no change in topological
polar surface area (TPSA). Combining these structural elements led
to the identification of 6-methyl-N-((1R)-1-(4-(trifluoromethoxy)­phenyl)­propyl)­pyrazolo­[1,5-a]­pyrimidine-3-carboxamide (38a), a molecule with the
desired balance of preclinical properties. Further characterization
by cocrystal structure analysis of 38a bound to PDE2A
uncovered a unique binding mode and provided insights into its observed
potency and PDE selectivity. Compound 38a significantly
elevated 3′,5′-cyclic guanosine monophosphate (cGMP)
levels in mouse brain following oral administration, thus validating
this compound as a useful pharmacological tool and an attractive lead
for future optimization.