title: 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.
authors.affiliation: Centro de Investigaciones Biológicas (CSIC) , Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: García
authors.forename: José
authors.initials: J
authors.lastname: Brea
authors.forename: Jose A
authors.initials: JA
authors.lastname: Morales-García
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Perez
authors.forename: Alejandro
authors.initials: A
authors.lastname: González
authors.forename: Sandra
authors.initials: S
authors.lastname: Alonso-Gil
authors.forename: Irene
authors.initials: I
authors.lastname: Gracia-Rubio
authors.forename: Clara
authors.initials: C
authors.lastname: Ros-Simó
authors.forename: Santiago
authors.initials: S
authors.lastname: Conde
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: Olga
authors.initials: O
authors.lastname: Valverde
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
mesh_terms: D000758:Anesthesia / Q000009:adverse effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010726:Phosphodiesterase Inhibitors; D013440:Sulfides; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517458:PDE7A protein, human