Modulation of cAMP-Specific PDE without Emetogenic Activity: New Sulfide-Like PDE7 Inhibitors
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- 作者：Ana M. Garc铆a ; Jos茅 Brea ; Jose A. Morales-Garc铆a ; Daniel I. Perez ; Alejandro Gonz谩lez ; Sandra Alonso-Gil ; Irene Gracia-Rubio ; Clara Ros-Sim贸 ; Santiago Conde ; Mar铆a Isabel Cadavid ; Mar铆a Isabel Loza ; Ana Perez-Castillo ; Olga Valverde ; Ana Martinez ; Carmen Gil
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：October 23, 2014
- 年：2014
- 卷：57
- 期：20
- 页码：8590-8607
- 全文大小：745K
- ISSN：1520-4804
文摘
A forward chemical genetic approach was followed to discover new targets and lead compounds for Parkinson鈥檚 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.