Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer's disease

Abstract

Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer's disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone derivatives, coupling with the pharmacophore of antioxidants such as ferulic and lipolic acids have been designed with the assistance of molecular docking and dynamics simulations. Twelve out of 14 synthesised compounds inhibited PDE9A with IC₅₀ below 200 nM, and showed good antioxidant capacities in the ORAC assay. Compound 1h, the most promising multifunctional anti-AD agent, had IC₅₀ of 56 nM against PDE9A and good antioxidant ability (ORAC (trolox) = 3.3). The selectivity of 1h over other PDEs was acceptable. In addition, 1h showed no cytotoxicity to human neuroblastoma SH-SY5Y cells. The analysis on structure-activity relationship (SAR) and binding modes of the compounds may provide insight into further modification.

Keywords: Alzheimer’s disease; Phosphodiesterase-9; antioxidant activity; molecular docking; multifunctional anti-AD agents.

Figure 1.

The design of PDE9 inhibitors with antioxidant activities.

Scheme 1.

Reagents and conditions: (a) Triethylamine, 0 °C, r.t., 3 h, then reflux 3 h, EtOH; (b) NH₃·H₂O,H₂O₂, EtOH, r.t.; (c) (R)-ethyl-2-(((benzyloxy)carbonyl)amino)propanoate, 60% NaH, dry THF, r.t.; (d) Pd/C, MeOH, H_2, r.t.; (e) EDC·HCl, DMAP, DMF, r.t.

Figure 2.

Cell viability of compounds 1h and 2.

Figure 3.

The binding modes of compounds 1h and 2.