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

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.
Elisa Zuccarello 1,  Hong Zhang 2,  Erica Acquarone 2,  Dang Pham 3,  Anna Staniszewski 2,  Shi-Xian Deng 4,  Donald W Landry 4,  Ottavio Arancio 5,  Jole Fiorito 6
Affiliations

Affiliations

  • 1 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, United States; Department of Medicine, Columbia University, New York, NY, United States.
  • 2 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, United States.
  • 3 New York Institute of Technology, Department of Biological and Chemical Sciences, Northern Boulevard, Old Westbury, NY 11568, United States.
  • 4 Department of Medicine, Columbia University, New York, NY, United States.
  • 5 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, United States; Department of Medicine, Columbia University, New York, NY, United States; Department of Pathology and Cell Biology, Columbia University, New York, NY, United States.
  • 6 New York Institute of Technology, Department of Biological and Chemical Sciences, Northern Boulevard, Old Westbury, NY 11568, United States; Department of Medicine, Columbia University, New York, NY, United States. Electronic address: [email protected].
PMID: 37453616 DOI: 10.1016/j.bmcl.2023.129409
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.

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