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

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.The authors gratefully acknowledge the financial support of Ministry of Science and Innovation (MICINN), projects nos. SAF2007-62811, SAF2009-13015-C02-01, SAF2009-08145 and SAF2010-16365; Instituto de Salud Carlos III (ISCiii), project no. RD07/0060/0015 and RD06/0026/0005 (RETICS program) and CIBERNED; Fundación Española para la Ciencia y la Tecnología (FECYT), project no. FCT-09-INC-0367 and Consejo Superior de Investigaciones Científicas (CSIC), project no. PIE 200780I012. M. R. and D. I. P. acknowledge pre- and post-doctoral fellowship from the CSIC (JAE program) respectively. J. G. Z. was supported by the Programme Alban, scholarship No. E07D400805CO. BRAINco Biopharma is acknowledged.Peer Reviewe