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Discovery of arylbenzylamines as PDE4 inhibitors with potential neuroprotective effect.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2019 Apr 15; Vol. 168, pp. 221-231. Date of Electronic Publication: 2019 Feb 11. - Publication Year :
- 2019
-
Abstract
- Growing evidence confirms the potential of PDE4 inhibitors for the treatment of Parkinson's disease. Our reported PDE4 inhibitors FCPR16 and FCPR03 have displayed neuroprotective effects in SH-SY5Y cells, but have very low oral bioavailability. To access analogues with improved bioavailability, a new series of arylbenzylamine derivatives were designed and synthesized. Preliminary screening results of the series showed that arylbenzylamine derivatives bearing a pyridin-3-amine side chain displayed good inhibitory activities against human PDE4B1 and PDE4D7 isoforms. Moreover, kinetic studies revealed that the most potent compounds 11r and 11s with mid-nanomolar IC <subscript>50</subscript> values partially bind to PDE4B1 (I <subscript>max</subscript> = 93% and 90% respectively). Molecular docking results revealed the possible interactions of compounds 11r and 11s with upstream conserved region 2 (UCR2) of PDE4B1, which illuminate possible reasons for their partial inhibition against PDE4. Using a cell-based model of PD, compounds 11r and 11s were found to alleviate cellular apoptosis in SH-SY5Y cells induced by MPP <superscript>+</superscript> (1-methyl-4-phenylpyridinium), with this neuroprotective effect being greater than PDE4 inhibitor rolipram. Furthermore, compound 11r displayed nearly sevenfold oral bioavailability (8.20%) than FCPR03 (1.23%).<br /> (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Animals
Benzylamines chemical synthesis
Benzylamines chemistry
Cell Survival drug effects
Dose-Response Relationship, Drug
Humans
Molecular Docking Simulation
Molecular Structure
Neuroprotective Agents chemical synthesis
Neuroprotective Agents chemistry
Parkinson Disease metabolism
Parkinson Disease pathology
Phosphodiesterase 4 Inhibitors chemical synthesis
Phosphodiesterase 4 Inhibitors chemistry
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Tumor Cells, Cultured
Benzylamines pharmacology
Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism
Drug Discovery
Neuroprotective Agents pharmacology
Parkinson Disease drug therapy
Phosphodiesterase 4 Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 168
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30822711
- Full Text :
- https://doi.org/10.1016/j.ejmech.2019.02.026