Modulation of cAMP-Specific PDE without Emetogenic Activity: New Sulfide-Like PDE7 Inhibitors

Abstract

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.

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

“…apremilast. The PDE7-GSK3 inhibitors used here (VP3.15 and VP1.15) have previously also shown an immunomodulatory effect in spinal cord injury models (as well as EAE)3436, without emetic side effects3640.…”

“…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. PDE7 inhibition leads to an enhancement of the intracellular levels of cAMP without intolerable gastrointestinal side effects40, making them potential and attractive therapeutic agents. Furthermore, glycogen synthase kinase 3 (GSK3) inhibition reduces the number of Th17 and Th1 cells with consequent alleviation of experimental autoimmune encephalomyelitis (EAE)4142.…”

PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis

“…Unfortunately, clinical trials with PDE4 inhibitors revealed major adverse effects of these drugs, namely nausea and vomiting (Robichaud et al ., ). PDE7 inhibitors are considered a good strategy to overcome these adverse effects with their more subtle modulation of cAMP levels (Giembycz, ) without emetogenic activity (Garcia et al ., ). We showed in the present study that TC3.6, a selective PDE7 inhibitor able to penetrate into the CNS (unpublished data), is efficacious at diminishing the symptoms and neuroinflammation in the Theiler's model of MS. Several studies have described changes in the expression of several PDE7 isoforms in the brain of rodents and humans in neurodegenerative diseases (Miro et al ., ; Perez‐Torres et al ., ; Reyes‐Irisarri et al ., ).…”

“…Moreover, recent studies showed that PDE7 inhibitors could play an anti‐inflammatory and neuroprotective role in cellular and animal models of Parkinson's disease (Morales‐Garcia et al ., ), spinal cord injury (Paterniti et al ., ), Alzheimer's disease (Perez‐Gonzalez et al ., ) and stroke (Redondo et al ., ). In addition, different chemically diverse PDE7 inhibitors have shown efficacy in the EAE model of MS (Redondo et al ., 2012a,b) without inducing emesis (Garcia et al ., ) pointing to a new era of innovative drugs. In this regard, the therapeutical potential for MS treatment of the thioxoquinazoline derivative TC3.6 synthesized in our laboratory has been recently reported.…”

Discovery of NovelSchistosoma MansoniPDE4A Inhibitors as Potential Agents against Schistosomiasis

“…Remarkably, iminothiadiazole NPD-01243 and NPD-0327 were previously described as human PDE7A inhibitors [52]. This human PDE is cAMP specific and its inhibitors, including these ones, have no emetic effects as those associated with PDE4 inhibition [53].…”