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Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer's disease.

Abstract Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer's disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone derivatives, coupling with the pharmacophore of antioxidants such as ferulic and lipolic acids have been designed with the assistance of molecular docking and dynamics simulations. Twelve out of 14 synthesised compounds inhibited PDE9A with IC50 below 200 nM, and showed good antioxidant capacities in the ORAC assay. Compound 1h, the most promising multifunctional anti-AD agent, had IC50 of 56 nM against PDE9A and good antioxidant ability (ORAC (trolox) = 3.3). The selectivity of 1h over other PDEs was acceptable. In addition, 1h showed no cytotoxicity to human neuroblastoma SH-SY5Y cells. The analysis on structure-activity relationship (SAR) and binding modes of the compounds may provide insight into further modification.
PMID
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Authors

Mayor MeshTerms

Drug Discovery

Keywords

Alzheimer’s disease

Phosphodiesterase-9

antioxidant activity

molecular docking

multifunctional anti-AD agents

Journal Title journal of enzyme inhibition and medicinal chemistry
Publication Year Start




PMID- 29271265
OWN - NLM
STAT- MEDLINE
DCOM- 20171229
LR  - 20171229
IS  - 1475-6374 (Electronic)
IS  - 1475-6366 (Linking)
VI  - 33
IP  - 1
DP  - 2018 Dec
TI  - Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of 
      Alzheimer's disease.
PG  - 260-270
LID - 10.1080/14756366.2017.1412315 [doi]
AB  - Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer's
      disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 
      inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone
      derivatives, coupling with the pharmacophore of antioxidants such as ferulic and 
      lipolic acids have been designed with the assistance of molecular docking and
      dynamics simulations. Twelve out of 14 synthesised compounds inhibited PDE9A with
      IC50 below 200 nM, and showed good antioxidant capacities in the ORAC assay.
      Compound 1h, the most promising multifunctional anti-AD agent, had IC50 of 56 nM 
      against PDE9A and good antioxidant ability (ORAC (trolox) = 3.3). The selectivity
      of 1h over other PDEs was acceptable. In addition, 1h showed no cytotoxicity to
      human neuroblastoma SH-SY5Y cells. The analysis on structure-activity
      relationship (SAR) and binding modes of the compounds may provide insight into
      further modification.
FAU - Zhang, Chen
AU  - Zhang C
AD  - a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , PR
      China.
FAU - Zhou, Qian
AU  - Zhou Q
AD  - a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , PR
      China.
FAU - Wu, Xu-Nian
AU  - Wu XN
AD  - a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , PR
      China.
FAU - Huang, Yat-Sen
AU  - Huang YS
AD  - a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , PR
      China.
FAU - Zhou, Jie
AU  - Zhou J
AD  - a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , PR
      China.
FAU - Lai, Zengwei
AU  - Lai Z
AD  - a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , PR
      China.
AD  - b State Key Laboratory for Chemistry and Molecular Engineering of Medicinal
      Resources , Guangxi Normal University , Guilin , PR China.
FAU - Wu, Yinuo
AU  - Wu Y
AD  - a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , PR
      China.
FAU - Luo, Hai-Bin
AU  - Luo HB
AD  - a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , PR
      China.
AD  - c Collaborative Innovation Center of High Performance Computing , National
      University of Defence Technology , Changsha , PR China.
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Enzyme Inhib Med Chem
JT  - Journal of enzyme inhibition and medicinal chemistry
JID - 101150203
RN  - 0 (Antioxidants)
RN  - 0 (Phosphodiesterase Inhibitors)
RN  - EC 3.1.4.17 (3',5'-Cyclic-AMP Phosphodiesterases)
RN  - EC 3.1.4.17 (PDE9A protein, human)
SB  - IM
MH  - 3',5'-Cyclic-AMP Phosphodiesterases/*antagonists & inhibitors/metabolism
MH  - Alzheimer Disease/*drug therapy/*enzymology
MH  - Antioxidants/chemical synthesis/chemistry/*pharmacology
MH  - Cell Line, Tumor
MH  - Dose-Response Relationship, Drug
MH  - *Drug Discovery
MH  - Humans
MH  - Models, Molecular
MH  - Molecular Structure
MH  - Phosphodiesterase Inhibitors/chemical synthesis/chemistry/*pharmacology
MH  - Structure-Activity Relationship
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - Phosphodiesterase-9
OT  - antioxidant activity
OT  - molecular docking
OT  - multifunctional anti-AD agents
EDAT- 2017/12/23 06:00
MHDA- 2017/12/30 06:00
CRDT- 2017/12/23 06:00
PHST- 2017/12/23 06:00 [entrez]
PHST- 2017/12/23 06:00 [pubmed]
PHST- 2017/12/30 06:00 [medline]
AID - 10.1080/14756366.2017.1412315 [doi]
PST - ppublish
SO  - J Enzyme Inhib Med Chem. 2018 Dec;33(1):260-270. doi:
      10.1080/14756366.2017.1412315.