Neuroprotective efficacy of quinazoline type phosphodiesterase 7 inhibitors in cellular cultures and experimental stroke model.

Abstract

A simple and efficient synthetic method for the preparation of quinazoline type phosphodiesterase 7 (PDE7) inhibitors, based on microwave irradiation, has been developed. The use of this methodology improved yields and reaction times, providing a scalable procedure. These compounds are pharmacologically interesting because of their in vivo efficacy both in spinal cord injury and Parkinson's disease models, as shown in previous studies from our group. Herein we describe for the first time that administration of one of the PDE7 inhibitors here optimized, 3-phenyl-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline (compound 5), ameliorated brain damage and improved behavioral outcome in a permanent middle cerebral artery occlusion (pMCAO) stroke model. Furthermore, we demonstrate that these PDE7 inhibitors are potent anti-inflammatory as well as neuroprotective agents in primary cultures of neural cells. These results led us to propose PDE7 inhibitors as a new class of therapeutic agents for neuroprotection.

• Authors: Miriam Redondo, Juan G Zarruk, Placido Ceballos, Daniel I Pérez, Concepción Pérez, Ana Perez-Castillo, María A Moro, José Brea, Cristina Val, María I Cadavid, María I Loza, Nuria E Campillo, Ana Martínez, Carmen Gil
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 47 Issue 1 Pg. 175-85 (Jan 2012) ISSN: 1768-3254 [Electronic] France
• PMID: 22100138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Neuroprotective Agents
• Quinazolines
• Cyclic Nucleotide Phosphodiesterases, Type 7

Topics

• Animals
• Blood-Brain Barrier (drug effects, metabolism)
• Cells, Cultured
• Cyclic Nucleotide Phosphodiesterases, Type 7 (antagonists & inhibitors)
• Disease Models, Animal
• Enzyme Inhibitors (chemistry, metabolism, pharmacology, therapeutic use)
• Infarction, Middle Cerebral Artery (drug therapy)
• Male
• Mice
• Neuroprotective Agents (chemistry, metabolism, pharmacology, therapeutic use)
• Permeability
• Quinazolines (chemistry, metabolism, pharmacology, therapeutic use)
• Stroke (drug therapy)