Phosphodiesterase Type 4 Inhibition in CNS Diseases

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Abstract

Phosphodiesterases (PDEs) have been an interesting drug target for many diseases. Although a vast number of mainly preclinical studies demonstrates beneficial effects of PDE inhibitors for central nervous system (CNS) diseases, no drugs are currently available for CNS indications. In this review, we discuss the rationale of PDE4 inhibitors for different CNS diseases, including memory impairments, striatal disorders, multiple sclerosis (MS), and acquired brain injury (ABU). However, clinical development has been problematic due to mechanism-based adverse effects of these drugs in humans. Our increased understanding of factors influencing the conformational state of the PDE4 enzyme and of how to influence the binding affinity of PDE4 subtype inhibitors, holds promise for the successful development of novel selective PDE4 inhibitors with higher efficacy and fewer adverse effects.

Original languageEnglish
Pages (from-to)971-985
Number of pages15
JournalTrends in Pharmacological Sciences
Volume40
Issue number12
DOIs
Publication statusPublished - Dec 2019

Keywords

  • SUBCELLULAR-LOCALIZATION
  • THERAPEUTIC STRATEGY
  • STRUCTURAL BASIS
  • DOUBLE-BLIND
  • CAMP
  • BRAIN
  • PDE4
  • MEMORY
  • BINDING
  • HIPPOCAMPUS

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