New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment

Chiara Brullo, Roberta Ricciarelli, Jos Prickaerts, Ottavio Arancio, Matteo Massa, Chiara Rotolo, Alessia Romussi, Claudia Rebosio, Barbara Marengo, Maria Adelaide Pronzato, Britt T J van Hagen, Nick P. van Goethem, Pasqualina D'Ursi, Alessandro Orro, Luciano Milanesi, Sara Guariento, Elena Cichero, Paola Fossa, Ernesto Fedele, Olga Bruno

Research output: Contribution to journalArticlepeer-review

Abstract

Phosphodiesterase type 4D (PDE4D) has been indicated as a promising target for treating neurodegenerative pathologies such as Alzheimer's Disease (AD). By preventing cAMP hydrolysis, PDE4 inhibitors (PDE4Is) increase the cAMP response element-binding protein (CREB) phosphorylation, synaptic plasticity and long-term memory formation. Pharmacological and behavioral studies on our hit GEBR-7b demonstrated that selective PDE4DIs could improve memory without causing emesis and sedation. The hit development led to new molecule series, herein reported, characterized by a catechol structure bonded to five member heterocycles. Molecular modeling studies highlighted the pivotal role of a polar alkyl chain in conferring selective enzyme interaction. Compound 8a showed PDE4D3 selective inhibition and was able to increase intracellular cAMP levels in neuronal cells, as well as in the hippocampus of freely moving rats. Furthermore, 8a was able to readily cross the blood-brain barrier and enhanced memory performance in mice without causing any emetic-like behavior. These data support the view that PDE4D is an adequate molecular target to restore memory deficits in different neuropathologies, including AD, and also indicate compound 8a as a promising candidate for further preclinical development.

Original languageEnglish
Pages (from-to)82-102
Number of pages21
JournalEuropean Journal of Medicinal Chemistry
Volume124
DOIs
Publication statusPublished - Nov 29 2016

Keywords

  • cAMP enhancers
  • In silico ADMET properties
  • Memory behavior test
  • Molecular dynamics simulation
  • PDE4D inhibitors
  • Pharmacokinetic analyses

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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