title: 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.
authors.affiliation: Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Redondo
authors.forename: José
authors.initials: J
authors.lastname: Brea
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Perez
authors.forename: Ignacio
authors.initials: I
authors.lastname: Soteras
authors.forename: Cristina
authors.initials: C
authors.lastname: Val
authors.forename: Concepción
authors.initials: C
authors.lastname: Perez
authors.forename: Jose A
authors.initials: JA
authors.lastname: Morales-García
authors.forename: Sandra
authors.initials: S
authors.lastname: Alonso-Gil
authors.forename: Nuria
authors.initials: N
authors.lastname: Paul-Fernandez
authors.forename: Rocío
authors.initials: R
authors.lastname: Martin-Alvarez
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Cadavid
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Loza
authors.forename: Ana
authors.initials: A
authors.lastname: Perez-Castillo
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Mengod
authors.forename: Nuria E
authors.initials: NE
authors.lastname: Campillo
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009103:Multiple Sclerosis / Q000188:drug therapy; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D061251:Primary Cell Culture; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005663:Furans; D007527:Isoenzymes; D018696:Neuroprotective Agents; D009573:Nitrites; D011994:Recombinant Proteins; D000242:Cyclic AMP; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517458:PDE7A protein, human; C517459:Pde7a protein, mouse