Poster presentado
PDE7 INHIBITORS AS NOVEL POTENTIAL DRUGS FOR NEURODEGENERATIVE DISORDERS
C. Gil1, M. Redondo1, C. Perez1, J.A. Morales-Garcia2, T. Castaño1, N. Campillo1, A. Perez-Castillo2, A. Martinez1
1CSIC, Instituto de Quimica Medica, Madrid, Spain, 2CSIC, Instituto de Investigaciones Biomedicas, Madrid, Spain
Phosphodiesterases (PDEs) play a central role in signal transduction by regulating intracellular levels of cyclic AMP (cAMP) and cGMP. There are 11 PDE families with differential tissue distribution [1]. In brain, PDE1, PDE4, PDE7 and PDE10 are highly expressed. Moreover, it has been suggested that cAMP pathways could be involved in Alzheimer´s and Parkinson's diseases interfering with both the inflammatory and neurotransmitter cascades [2]. Therefore, selective inhibitors of these PDEs could represent a novel approach to treat these devastating diseases. Furthermore, PDE4 and PDE10 inhibitors have started clinical trials for AD as cognitive enhancers being involved in synaptic plasticity by modulation of cAMP signaling.
Using different drug design techniques, we have discovered chemical diverse specific PDE7 inhibitors [3] that increase cAMP levels and present neuroprotective properties in a number of cellular models. Evidence that these compounds have potent anti-inflammatory effects both in macrophage cell line and primary astrocytes treated with lipopolysaccharide (LPS), as measured by a nitrite liberation assay will be here reported, together with their discovery, biological profile and in silico ADME properties. This study emphasizes the potential use of PDE7 inhibitors as neurodegenerative diseases therapy.
[1] Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide PDEs: essential components in cyclic nucleotide signaling. Annu. Rev. Biochem. 2007, 76:481-511.
[2] Menniti FS, et al. PDEs in the CNS: targets for drug development. Nat. Rev. Drug Discov. 2006, 5:660-70.
[3] Castro A, et al. CODES, a novel procedure for ligand-based virtual screening: PDE7 inhibitors. Eur. J. Med. Chem. 2008, 43:1349-59.