New selective phosphodiesterase 4D inhibitors differently acting on long, short, and supershort isoforms.

Abstract

The lack of selective inhibitors toward the long, short, or supershort phosphodiesterases (PDE4s) prevented researchers from carefully defining the connection between different enzyme isoforms, their brain localization, and their role in neurodegenerative diseases such as Alzheimer's disease (AD). In the search for new therapeutic agents for treating memory and learning disorders, we synthesized new rolipram related PDE4 inhibitors, which had some selectivity toward the long form PDE4D3. The first series was synthesized as racemate and then resolved by semipreparative HPLC on chiral supports. Herein we report the synthetic pathways to obtain compounds 1a-c, 2a-c, 3a-c, 4a-f, 5a,b, 6a,b, 7a,b, the chiral analytical study to resolve compounds 1a-c, 2a-c, 3a-c, the molecular docking study for compound 1c, and the biological results and some SAR considerations that provide some insights and hints for the structural requirements for PDE4D subtype selectivity and enzyme inhibition.

• Authors: Olga Bruno, Alessia Romussi, Andrea Spallarossa, Chiara Brullo, Silvia Schenone, Francesco Bondavalli, Nicolas Vanthuyne, Christian Roussel
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 21 Pg. 6546-57 (Nov 12 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19827751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzaldehydes
• Cyclopentanes
• Isoenzymes
• Morpholines
• Phosphodiesterase 4 Inhibitors
• Recombinant Proteins
• Cyclic Nucleotide Phosphodiesterases, Type 4
• Rolipram

Topics

• Benzaldehydes (chemical synthesis, chemistry)
• Binding Sites
• Cyclic Nucleotide Phosphodiesterases, Type 4 (chemistry)
• Cyclopentanes (chemical synthesis, chemistry)
• Humans
• Isoenzymes (antagonists & inhibitors, chemistry)
• Models, Molecular
• Molecular Conformation
• Morpholines (chemical synthesis, chemistry)
• Phosphodiesterase 4 Inhibitors
• Recombinant Proteins (antagonists & inhibitors, chemistry)
• Rolipram (analogs & derivatives, chemical synthesis, chemistry)
• Stereoisomerism
• Structure-Activity Relationship