Search

et al., A forward chemical genetic approach was followed to discover new targets and lead compounds for Parkinson's disease (PD) treatment. By analysis of the cell protection produced by some small molecules, a diphenyl sulfide compound was revealed to be a new phosphodiesterase 7 (PDE7) inhibitor and identified as a new hit. This result allows us to confirm the utility of PDE7 inhibitors as a potential pharmacological treatment of PD. On the basis of these data, a diverse family of diphenyl sulfides has been developed and pharmacologically evaluated in the present work. Moreover, to gain insight into the safety of PDE7 inhibitors for human chronic treatment, we evaluated the new compounds in a surrogate emesis model, showing nonemetic effects., Financial support from MINECO and FEDER founds (UE program) (project nos. IPT-2012-0762-300000 and SAF2012-33600) and MICINN (SAF2010-15793 to O.V. and SAF2010-16365 to A.P.-C.) are acknowledged. A.M.G. and D. I. P. acknowledge a predoctoral and postdoctoral grants respectively to the CSIC (JAE program). CIBERNED is funded by the Instituto de Salud Carlos III. J.A.M-G. is a fellow from CIBERNED. BRAINco Biopharma SL reviewed and funded the pro-emetic studies of rolipram, roflumilast, BRL50481, VP1.15, and TC3.6 compounds.

Phosphodiesterase (PDE) 7 is involved in proinflammatory processes, being widely expressed both on lymphocytes and on certain brain regions. Specific inhibitors of PDE7 have been recently reported as potential new drugs for the treatment of neurological disorders because of their ability to increase intracellular levels of cAMP and thus to modulate the inflammatory process, as a neuroprotective well-established strategy. Multiple sclerosis is an unmet disease in which pathologies on the immune system, T-cells, and specific neural cells are involved simultaneously. Therefore, PDE7 inhibitors able to interfere with all these targets may represent an innovative therapy for this pathology. Here, we report a new chemically diverse family of heterocyclic PDE7 inhibitors, discovered and optimized by using molecular modeling studies, able to increase cAMP levels in cells, decrease inflammatory activation on primary neural cultures, and also attenuate the clinical symptoms in the experimental autoimmune encephalomyelitis (EAE) mouse model. These results led us to propose the use of PDE7 inhibitors as innovative therapeutic agents for the treatment of multiple sclerosis. © 2012 American Chemical Society., The authors gratefully acknowledge the financial support of Ministry of Science and Innovation (MICINN), projects nos. SAF2009-13015-C02-01, SAF2009-13015-C02-02, SAF2010-16365, SAF2009-1152, and PI10-01874; Instituto de Salud Carlos III (ISCiii), project no. RD07/0060/0015 (RETICS program) and CIBERNED; Fundación Española para la Ciencia y la Tecnología (FECYT), project no. FCT-09-INC-0367. M.R. and D. I. P. acknowledge pre- and post-doctoral fellowship from the CSIC (JAE program) respectively.

et al., Herein we present a new family of melatonin-based compounds, in which the acetamido group of melatonin has been bioisosterically replaced by a series of reversed amides and azoles, such as oxazole, 1,2,4-oxadiazole, and 1,3,4-oxadiazole, as well as other related five-membered heterocycles, namely, 1,3,4-oxadiazol(thio)ones, 1,3,4-triazol(thio)ones, and an 1,3,4-thiadiazole. New compounds were fully characterized at melatonin receptors (MT1R and MT2R), and results were rationalized by superimposition studies of their structures to the bioactive conformation of melatonin. We also found that several of these melatonin-based compounds promoted differentiation of rat neural stem cells to a neuronal phenotype in vitro, in some cases to a higher extent than melatonin. This unique profile constitutes the starting point for further pharmacological studies to assess the mechanistic pathways and the relevance of neurogenesis induced by melatonin-related structures., We gratefully acknowledge the financial support of the Spanish Ministry of Economy and Competitiveness (MINECO, Grants SAF2012-31035, SAF2010-16365, and SAF2014-52940-R), Fundación de Investigación Médica Mutua Madrileña Automovilística (Grant AP103952012), and Consejo Superior de Investigaciones Científicas (CSIC, Grant PIE-201280E074). The Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) is funded by the Instituto de Salud Carlos III. M.d.l.F.R. thanks CSIC for a JAE-Predoctoral Contract, and J.A.M.-G. thanks CIBERNED for a postdoctoral fellowship . We also acknowledge Dr. Paula Morales for the binding assays on cannabinoid receptors and the National Institute on Mental Health-Psychoactive Drug Screening Program (NIMH-PDSP, Contract HHSN-271-2013-00017-C, Dr. Bryan Roth) for binding experiments on serotonin receptors and transporter.