Discovery of Potent, Selective, and Orally Bioavailable Inhibitors against Phosphodiesterase-9, a Novel Target for the Treatment of Vascular Dementia

Abstract

To identify phosphodiesterase-9 (PDE9) as a novel target for the treatment of vascular dementia (VaD), a series of pyrazolopyrimidinone analogues were discovered based on a hit 1. Hit-to-lead optimization resulted in a potent inhibitor 2 with excellent selectivity and physicochemical properties to enable in vivo studies. Oral administration of 2 (5.0 mg/kg) caused notable therapeutic effects in the VaD mouse model, providing a promising lead or chemical probe for investigating the biological functions of PDE9 inhibition.

Discovery of Potent Phosphodiesterase-9 Inhibitors for the Treatment of Hepatic Fibrosis

“…In our studies aiming to discover novel PDE9 inhibitors and their novel potential therapeutic applications, a hit compound LL01 with an IC 50 value of 49 nM and a moderate T 1/2 of 8.03 min in rat liver microsomes (RLMs) was developed. 16 To obtain lead compounds with better microsomal stability, further structural optimization of compound LL01 was performed via structurebased design approaches such as molecular docking and dynamics simulations, which allowed us to save our synthetic efforts. A redocking of the inhibitor 28 s in the crystal structure (PDB ID: 4GH6) was performed to validate the docking approach suitable for PDE9.…”

“…described in our previous report. 16 3 H-cGMP was the substrate for the biological test using PDE9A2. 3 H-cGMP was diluted with the assay buffer, which contained 20−50 mM Tris−HCl (pH 8.0), 10 mM MgCl 2 , and 1 mM dithiothreitol to 20,000−30,000 cpm per assay.…”

“…Among all the PDE subfamilies, PDE9 is a cGMP-specific PDE member with the highest affinity for cGMP ( K m = 170 nM), indicating that the PDE9 inhibitor might be highly effective in cGMP-related diseases. − However, research studies on the development of PDE9 inhibitors are relatively few compared with those on other PDE subfamilies, and most PDE9 inhibitors were applied for the treatment of Alzheimer’s diseases. − We hypothesized that PDE9 inhibitors could ameliorate hepatic fibrosis via the activation of cGMP/protein kinase G signaling and thus represent a novel therapy for hepatic fibrosis. Herein, structure-based optimizations from a starting hit LL01 were performed with the assistance of molecular docking and dynamic simulations, yielding a series of PDE9 inhibitors with higher inhibitory potency, excellent isoform selectivity, and remarkable microsomal stability.…”

Discovery of Dipyridamole Analogues with Enhanced Metabolic Stability for the Treatment of Idiopathic Pulmonary Fibrosis

“…Our previous studies suggested that introducing certain heterocyclic rings (especially those containing fluorine atoms), other than piperidine rings, were useful for the improved metabolic stability of PDE inhibitors [ 17 , 18 ]. For DIP, its piperidine rings made fewer key interactions than diethanolamine chains with PDE5.…”

Network pharmacology and the experimental findings of Bushenhuoxue formula for improving hippocampal neuron injury in vascular demented rats

“…Some stud-ies have even shown that VD coexists in clinical patients with Alzheimer's disease; the combination often increases the difficulty of treatment [5]. VD is the only type of dementia that can be prevented by early treatment [6]. Risk factors for VD development include hyperlipidemia, hypertension, diabetes mellitus, and tobacco use.…”