Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders

J Med Chem. 2019 May 23;62(10):4884-4901. doi: 10.1021/acs.jmedchem.9b00193. Epub 2019 Apr 23.


Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Behavior, Animal / drug effects
  • Brain Diseases / drug therapy*
  • Brain Diseases / enzymology
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Drug Design*
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / enzymology
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Mice, Inbred ICR
  • Molecular Structure
  • Phosphodiesterase 4 Inhibitors / chemical synthesis*
  • Phosphodiesterase 4 Inhibitors / chemistry
  • Phosphodiesterase 4 Inhibitors / pharmacology
  • Structure-Activity Relationship


  • Phosphodiesterase 4 Inhibitors
  • Cyclic Nucleotide Phosphodiesterases, Type 4