Optimizing metabolic stability of phosphodiesterase 5 inhibitors: Discovery of a potent N-(pyridin-3-ylmethyl)quinoline derivative targeting synaptic plasticity

Bioorg Med Chem Lett. 2023 Aug 15:92:129409. doi: 10.1016/j.bmcl.2023.129409. Epub 2023 Jul 13.

Abstract

Phosphodiesterase 5 (PDE5) is a cyclic guanosine monophosphate-degrading enzyme involved in numerous biological pathways. Inhibitors of PDE5 are important therapeutics for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). We previously reported the first generation of quinoline-based PDE5 inhibitors for the treatment of AD. However, the short in vitro microsomal stability rendered them unsuitable drug candidates. Here we report a series of new quinoline-based PDE5 inhibitors. Among them, compound 4b, 8-cyclopropyl-3-(hydroxymethyl)-4-(((6-methoxypyridin-3-yl)methyl)amino)quinoline-6-carbonitrile, shows a PDE5 IC50 of 20 nM and improved in vitro microsomal stability (t1/2 = 44.6 min) as well as excellent efficacy in restoring long-term potentiation, a type of synaptic plasticity to underlie memory formation, in electrophysiology experiments with a mouse model of AD. These results provide an insight into the development of a new class of PDE5 inhibitors for the treatment of AD.

Keywords: Human liver microsomes; Metabolic stability; PDE5 inhibitors; Quinoline derivatives; Tau protein; cGMP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Animals
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
  • Mice
  • Neuronal Plasticity
  • Phosphodiesterase 5 Inhibitors / pharmacology
  • Quinolines* / pharmacology
  • Quinolines* / therapeutic use

Substances

  • Phosphodiesterase 5 Inhibitors
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Quinolines