Discovery of a Phosphodiesterase 9A Inhibitor as a Potential Hypoglycemic Agent

Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimer’s disease. Here we report a potent PDE9 inhibitor <b>3r</b> that has an IC₅₀ of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that <b>3r</b> inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of <b>3r</b>, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-<b>3r</b> reveals significantly different conformation and hydrogen bonding pattern of <b>3r</b> from those of previously published <b>28s</b>. Both <b>3r</b> and <b>28s</b> form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but <b>3r</b> shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors