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Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2021 Nov 05; Vol. 223, pp. 113638. Date of Electronic Publication: 2021 Jun 13. - Publication Year :
- 2021
-
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.<br />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.<br /> (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 223
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34171658
- Full Text :
- https://doi.org/10.1016/j.ejmech.2021.113638