... una vez realizadas las tres presentaciones ... es hora de discutirlas entre los colegas de profesion y ver si sacan conclusiones ... y a esperar si desde Noscira ( Zeltia ) dan un comunicado .
Poster presentado :
MARINE NATURAL PRODUCTS AS Aβ MODULATORS
E. García-Palomero, P. Usán, P. García, E. Delgado, C. de Austria, G. Sáiz, M.A. Pérez, J. Sánchez-Quesada, I. Dorronsoro, A. Castro, M. Medina
NOSCIRA S.A., Tres Cantos, Spain
Aims: A growing body of evidence implicates oxidative stress in cellular mechanisms leading to neuronal cell death associated to certain neurodegenerative conditions such as AD or PD. Thus, neuroprotection approaches constitute promising attempts to slow the progression of some neurodegenerative processes. The marine environment represents an enormous resource for the discovery of potential chemotherapeutic agents. Thus, we have developed a drug discovery program in order to look for neuroprotectant marine compounds.
Methods: We have performed a systematic screening program aimed at isolating compounds from marine organisms showing neuroprotective activities against neuronal cell death induced by oxidative stress.
Results: These marine compounds are able to significantly reduce β-amyloid secretion in a number of APP-transfected cell lines. This effect correlates with an increase of sAPPα, suggesting that is mediated by the activation of the α-secretase pathway. Another interesting property of these compounds has been evaluated: their capacity to activate metalloproteases which are implicated in the β-amyloid degradation. An active medicinal chemistry program has been developed, leading to several naturally-derived, synthetic lead compounds with improved potencies and ADME properties. The basic pharmacokinetics parameters have been determined in rodents for some of these compoundsshowing that they are orally bioavailable, and are able to cross the blood brain barrier. In vivo proof of efficacy studies are currently being carried out in different animal models of neurodegenerative diseases.
Conclusion: This family of compounds could be of use in the preparation of drugs for the treatment and/or prevention of oxidative stress-induced diseases or conditions, especially neurodegenerative diseases.
14 marzo 2009
Noscira , Segunda presentacion en el Congreso Alzheimer realizada hoy a las 10,15 AM .
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.
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.
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