1. Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors.
- Author
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Brullo C, Rapetti F, Abbate S, Prosdocimi T, Torretta A, Semrau M, Massa M, Alfei S, Storici P, Parisini E, and Bruno O
- Subjects
- Binding Sites, Catalytic Domain, Crystallography, X-Ray, Cyclic AMP metabolism, Cyclic Nucleotide Phosphodiesterases, Type 4 chemistry, Cyclic Nucleotide Phosphodiesterases, Type 4 genetics, Humans, Molecular Docking Simulation, Phosphodiesterase 4 Inhibitors chemistry, Phosphodiesterase 4 Inhibitors metabolism, Protein Isoforms antagonists & inhibitors, Protein Isoforms metabolism, Recombinant Proteins biosynthesis, Recombinant Proteins chemistry, Recombinant Proteins isolation & purification, Small Molecule Libraries chemical synthesis, Small Molecule Libraries metabolism, Structure-Activity Relationship, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, Drug Design, Phosphodiesterase 4 Inhibitors chemical synthesis, Small Molecule Libraries chemistry
- Abstract
Memory and cognitive functions depend on the cerebral levels of cyclic adenosine monophosphate (cAMP), which are regulated by the phosphodiesterase 4 (PDE4) family of enzymes. Selected rolipram-related PDE4 inhibitors, members of the GEBR library, have been shown to increase hippocampal cAMP levels, providing pro-cognitive benefits with a safe pharmacological profile. In a recent SAR investigation involving a subset of GEBR library compounds, we have demonstrated that, depending on length and flexibility, ligands can either adopt a twisted, an extended or a protruding conformation, the latter allowing the ligand to form stabilizing contacts with the regulatory domain of the enzyme. Here, based on those findings, we describe further chemical modifications of the protruding subset of GEBR library inhibitors and their effects on ligand conformation and potency. In particular, we demonstrate that the insertion of a methyl group in the flexible linker region connecting the catechol portion and the basic end of the molecules enhances the ability of the ligand to interact with both the catalytic and the regulatory domains of the enzyme., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
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