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

• Published in: Journal of medicinal chemistry 2012-04, Vol.55 (7), p.3274-3284
• Main Authors: Redondo, Miriam, Brea, José, Perez, Daniel I, Soteras, Ignacio, Val, Cristina, Perez, Concepción, Morales-García, Jose A, Alonso-Gil, Sandra, Paul-Fernandez, Nuria, Martin-Alvarez, Rocío, Cadavid, María Isabel, Loza, María Isabel, Perez-Castillo, Ana, Mengod, Guadalupe, Campillo, Nuria E, Martinez, Ana, Gil, Carmen
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Blood-Brain Barrier - metabolism; Cell Survival - drug effects; Cyclic AMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 7 - antagonists & inhibitors; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - enzymology; Female; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; Humans; Isoenzymes - antagonists & inhibitors; Mice; Mice, Inbred C57BL; Models, Molecular; Multiple Sclerosis - drug therapy; Neuroglia - cytology; Neuroglia - drug effects; Neuroglia - metabolism; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Nitrites - metabolism; Primary Cell Culture; Rats; Recombinant Proteins - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm201720d

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.