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Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2015 Jul 01; Vol. 23 (13), pp. 3426-35. Date of Electronic Publication: 2015 Apr 16. - Publication Year :
- 2015
-
Abstract
- A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Catechols blood
Catechols chemical synthesis
Cell Line, Tumor
Cell Survival drug effects
Cyclic Nucleotide Phosphodiesterases, Type 4 chemistry
Diazepam blood
Diazepam pharmacokinetics
Enzyme Assays
Gene Expression
Halogenation
Humans
Isoenzymes antagonists & inhibitors
Isoenzymes chemistry
Isoenzymes metabolism
Male
Mice
Mice, Inbred BALB C
Motor Activity drug effects
Neurons cytology
Neurons enzymology
Nootropic Agents blood
Nootropic Agents chemical synthesis
Phosphodiesterase Inhibitors blood
Phosphodiesterase Inhibitors chemical synthesis
Rolipram blood
Rolipram pharmacokinetics
Structure-Activity Relationship
Catechols pharmacokinetics
Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism
Neurons drug effects
Nootropic Agents pharmacokinetics
Phosphodiesterase Inhibitors pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 23
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25936260
- Full Text :
- https://doi.org/10.1016/j.bmc.2015.04.027