Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer's disease

作者：Rabal Obdulia; Sanchez Arias Juan A; Cuadrado Tejedor Mar; de Miguel Irene; Perez Gonzalez Marta; Garcia Barroso Carolina; Ugarte Ana; Estella Hermoso de Mendoza Ander; Saez Elena; Espelosin Maria; Ursua Susana; Tan Haizhong; Wei Wu; Xu Musheng; Garcia Osta Ana; Oyarzabal Julen^*

来源：European Journal of Medicinal Chemistry, 2018, 150: 506-524.

DOI：10.1016/j.ejmech.2018.03.005

• Dual inhibitors
• PDE5 inhibition
• HDAC6 selective
• Alzheimer
• Pharmacological tool compound
• Tg2576 mice
• In-vivo test

We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo.

• 出版日期2018-4-25