Effect of Phosphodiesterase 7 (PDE7) Inhibitors in Experimental Autoimmune Encephalomyelitis Mice. Discovery of a New Chemically Diverse Family of Compounds

Abstract

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.

Silencing phosphodiesterase 7B gene by lentiviral-shRNA interference attenuates neurodegeneration and motor deficits in hemiparkinsonian mice

“…Importantly, depletion of PDE7B levels by lentiviral delivery of PDE7 shRNA significantly ameliorates the motor impairment subsequent to dopaminergic cell loss. Previous results from our group demonstrate that chemical inhibition of PDE7 trigger neuroprotection and diminish neuroinflammation in different models of brain diseases, including PD (Castano et al, 2009;Morales-Garcia et al, 2011;Redondo et al, 2012;Susin et al, 2012). Other authors have shown a Fig.…”

“…Given the important role of cAMP in the brain, specific inhibitors of PDEs are being analyzed as possible therapeutic targets for the treatment of different brain diseases (Garcia-Osta et al, 2012;Menniti et al, 2006;Sharma et al, 2013). During the last years, we have shown that different inhibitors of PDE7 are potent neuroprotective and anti-inflammatory agents in several animal models of neurodegenerative disorders, including PD (Castano et al, 2009;MoralesGarcia et al, 2011;Redondo et al, 2012;Susin et al, 2012).…”

Promoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis

“…In this context, we have recently shown the anti-inflammatory and neuroprotective effects of the cAMP-specific phosphodiesterase 7 (PDE7) inhibitors in animal models of spinal cord injury, stroke, Parkinson´s and Alzheimer´s diseases, and MS29303132333435363738. Although their effect on remyelination remains unknown, previous data from our group have shown that PDE7 inhibitors favour the differentiation and survival of mouse cortical OPCs and the differentiation of adult human OPCs in vitro 39.…”

Identification in Silico and Experimental Validation of Novel Phosphodiesterase 7 Inhibitors with Efficacy in Experimental Autoimmune Encephalomyelitis Mice

“…20 More recently, we have reported also in vivo efficacy of the furan type PDE7 inhibitors in an animal model of multiple sclerosis. 11 Herein, we describe the development of a neuronal network model in order to predict the inhibitory activity of new compounds on PDE7. Using this computational approach, we present the discovery of a new chemical family of PDE7 inhibitors, the 5-imino-1,2,4-thiadiazoles (ITDZs) recently described in our group as substrate competitive GSK-3 inhibitors.…”

“…As aqueous solubility of lipophilic scaffolds is often improved by the attachment of a morpholine unit, 46 we selected derivative 15 containing this unit, as candidate for further progression. Its capacity to cross the BBB 21 and its safety in the Ames test, prompted us to evaluate it in chronic experimental autoimmune encephalomyelitis (EAE) mice, a well established murine model for multiple sclerosis where GSK3β 22 and PDE7 inhibitors 11 have shown separately efficacy.…”